AU2022218486A1 - Process for making arylomyin ring analogs - Google Patents
Process for making arylomyin ring analogs Download PDFInfo
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- AU2022218486A1 AU2022218486A1 AU2022218486A AU2022218486A AU2022218486A1 AU 2022218486 A1 AU2022218486 A1 AU 2022218486A1 AU 2022218486 A AU2022218486 A AU 2022218486A AU 2022218486 A AU2022218486 A AU 2022218486A AU 2022218486 A1 AU2022218486 A1 AU 2022218486A1
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- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 63
- 230000008569 process Effects 0.000 title description 4
- 239000012453 solvate Substances 0.000 claims abstract description 119
- 150000003839 salts Chemical class 0.000 claims abstract description 117
- 150000001875 compounds Chemical class 0.000 claims description 162
- 125000000217 alkyl group Chemical group 0.000 claims description 93
- 125000005843 halogen group Chemical group 0.000 claims description 72
- 229910052739 hydrogen Inorganic materials 0.000 claims description 63
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 53
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 52
- 239000001257 hydrogen Substances 0.000 claims description 48
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 31
- 125000006239 protecting group Chemical group 0.000 claims description 31
- 239000003153 chemical reaction reagent Substances 0.000 claims description 28
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 18
- 125000006242 amine protecting group Chemical group 0.000 claims description 15
- 150000001413 amino acids Chemical class 0.000 claims description 13
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- 125000004429 atom Chemical group 0.000 claims description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- BGJSXRVXTHVRSN-UHFFFAOYSA-N 1,3,5-trioxane Chemical compound C1OCOCO1 BGJSXRVXTHVRSN-UHFFFAOYSA-N 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 230000002140 halogenating effect Effects 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 230000002152 alkylating effect Effects 0.000 claims description 3
- 108010011222 cyclo(Arg-Pro) Proteins 0.000 claims description 2
- -1 phenyl boronate compound Chemical class 0.000 description 109
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 69
- 239000000203 mixture Substances 0.000 description 64
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 55
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 47
- 238000006243 chemical reaction Methods 0.000 description 46
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 45
- 239000007787 solid Substances 0.000 description 44
- 239000000243 solution Substances 0.000 description 44
- 125000002947 alkylene group Chemical group 0.000 description 42
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 38
- 125000000753 cycloalkyl group Chemical group 0.000 description 36
- 238000005481 NMR spectroscopy Methods 0.000 description 32
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 31
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 27
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 27
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 25
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 23
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 22
- 238000005859 coupling reaction Methods 0.000 description 22
- 235000019439 ethyl acetate Nutrition 0.000 description 22
- BWHDROKFUHTORW-UHFFFAOYSA-N tritert-butylphosphane Chemical compound CC(C)(C)P(C(C)(C)C)C(C)(C)C BWHDROKFUHTORW-UHFFFAOYSA-N 0.000 description 22
- 150000001408 amides Chemical class 0.000 description 21
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 21
- 238000004128 high performance liquid chromatography Methods 0.000 description 20
- 239000012074 organic phase Substances 0.000 description 20
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 19
- 235000001014 amino acid Nutrition 0.000 description 19
- 239000012071 phase Substances 0.000 description 19
- 239000011541 reaction mixture Substances 0.000 description 19
- 230000008878 coupling Effects 0.000 description 18
- 238000010168 coupling process Methods 0.000 description 18
- 239000011734 sodium Substances 0.000 description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- 239000000706 filtrate Substances 0.000 description 16
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 15
- 239000002002 slurry Substances 0.000 description 15
- 239000002904 solvent Substances 0.000 description 15
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 14
- 125000003545 alkoxy group Chemical group 0.000 description 14
- 125000001309 chloro group Chemical group Cl* 0.000 description 14
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 14
- 238000003756 stirring Methods 0.000 description 14
- 230000015572 biosynthetic process Effects 0.000 description 13
- 201000010099 disease Diseases 0.000 description 13
- 239000003880 polar aprotic solvent Substances 0.000 description 13
- 239000000725 suspension Substances 0.000 description 13
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 12
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 12
- 239000003208 petroleum Substances 0.000 description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 12
- 125000003118 aryl group Chemical group 0.000 description 11
- 125000001072 heteroaryl group Chemical group 0.000 description 11
- 238000010966 qNMR Methods 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 10
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 10
- GPIQOFWTZXXOOV-UHFFFAOYSA-N 2-chloro-4,6-dimethoxy-1,3,5-triazine Chemical compound COC1=NC(Cl)=NC(OC)=N1 GPIQOFWTZXXOOV-UHFFFAOYSA-N 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 9
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 9
- 239000012267 brine Substances 0.000 description 9
- 125000004432 carbon atom Chemical group C* 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- 238000004949 mass spectrometry Methods 0.000 description 9
- 229910052757 nitrogen Inorganic materials 0.000 description 9
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 9
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 8
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 8
- 125000000623 heterocyclic group Chemical group 0.000 description 8
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 7
- 239000007821 HATU Substances 0.000 description 7
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 7
- 238000010511 deprotection reaction Methods 0.000 description 7
- 230000026030 halogenation Effects 0.000 description 7
- 238000005658 halogenation reaction Methods 0.000 description 7
- 239000010410 layer Substances 0.000 description 7
- 229910052763 palladium Inorganic materials 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- 239000000523 sample Substances 0.000 description 7
- FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- 239000004215 Carbon black (E152) Substances 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 229930195733 hydrocarbon Natural products 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 230000002829 reductive effect Effects 0.000 description 6
- PPYIWZLTNLCBQS-HNNXBMFYSA-N (2S)-2-(4-hydroxy-3-iodophenyl)-2-[methyl(phenylmethoxycarbonyl)amino]acetic acid Chemical compound C(C1=CC=CC=C1)OC(=O)N([C@H](C(=O)O)C1=CC(=C(C=C1)O)I)C PPYIWZLTNLCBQS-HNNXBMFYSA-N 0.000 description 5
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- 241000124008 Mammalia Species 0.000 description 5
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 5
- 238000007792 addition Methods 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 5
- DFNYGALUNNFWKJ-UHFFFAOYSA-N aminoacetonitrile Chemical compound NCC#N DFNYGALUNNFWKJ-UHFFFAOYSA-N 0.000 description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 5
- 150000007942 carboxylates Chemical group 0.000 description 5
- 235000019441 ethanol Nutrition 0.000 description 5
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 5
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 4
- ZNOVTXRBGFNYRX-UHFFFAOYSA-N 2-[[4-[(2-amino-5-methyl-4-oxo-1,6,7,8-tetrahydropteridin-6-yl)methylamino]benzoyl]amino]pentanedioic acid Chemical compound C1NC=2NC(N)=NC(=O)C=2N(C)C1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 ZNOVTXRBGFNYRX-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Natural products OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 125000004103 aminoalkyl group Chemical group 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 125000001188 haloalkyl group Chemical group 0.000 description 4
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropyl acetate Chemical compound CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 4
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 4
- 150000002825 nitriles Chemical class 0.000 description 4
- 125000006413 ring segment Chemical group 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 description 4
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 4
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- WIDLDIKWHWFNOR-UHFFFAOYSA-N 2-[3-[5-[2-(2-aminopropanoylamino)-3-methoxy-3-oxopropyl]-2-phenylmethoxyphenyl]-4-hydroxyphenyl]-2-[methyl(phenylmethoxycarbonyl)amino]acetic acid Chemical compound COC(=O)C(CC1=CC=C(OCC2=CC=CC=C2)C(=C1)C1=C(O)C=CC(=C1)C(N(C)C(=O)OCC1=CC=CC=C1)C(O)=O)NC(=O)C(C)N WIDLDIKWHWFNOR-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
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- 241001465754 Metazoa Species 0.000 description 3
- 238000006069 Suzuki reaction reaction Methods 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000005804 alkylation reaction Methods 0.000 description 3
- 125000003710 aryl alkyl group Chemical group 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 125000001246 bromo group Chemical group Br* 0.000 description 3
- 125000000392 cycloalkenyl group Chemical group 0.000 description 3
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 125000002346 iodo group Chemical group I* 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
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- 125000001424 substituent group Chemical group 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- RZIZYJRHLBXFEA-AWEZNQCLSA-N (2S)-2-(4-hydroxy-3-iodophenyl)-2-(phenylmethoxycarbonylamino)acetic acid Chemical compound C(C1=CC=CC=C1)OC(=O)N[C@H](C(=O)O)C1=CC(=C(C=C1)O)I RZIZYJRHLBXFEA-AWEZNQCLSA-N 0.000 description 2
- LIWKOFAHRLBNMG-FQEVSTJZSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-4-[(2-methylpropan-2-yl)oxycarbonylamino]butanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](CCNC(=O)OC(C)(C)C)C(O)=O)C3=CC=CC=C3C2=C1 LIWKOFAHRLBNMG-FQEVSTJZSA-N 0.000 description 2
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- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 2
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- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 2
- QKSGIGXOKHZCQZ-UHFFFAOYSA-N 2-chloro-2-phenylacetic acid Chemical compound OC(=O)C(Cl)C1=CC=CC=C1 QKSGIGXOKHZCQZ-UHFFFAOYSA-N 0.000 description 2
- UQTZMGFTRHFAAM-ZETCQYMHSA-N 3-iodo-L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(I)=C1 UQTZMGFTRHFAAM-ZETCQYMHSA-N 0.000 description 2
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- RWKOSHFCGWENBL-UBVMKEEMSA-N [5-[(2S)-2-[[(2S)-2-[[(2S)-2-(4-hydroxy-3-iodophenyl)-2-[methyl(phenylmethoxycarbonyl)amino]acetyl]amino]propanoyl]amino]-3-methoxy-3-oxopropyl]-2-phenylmethoxyphenyl]boronic acid Chemical compound C(C1=CC=CC=C1)OC1=C(C=C(C=C1)C[C@H](NC([C@@H](NC([C@@H](N(C(OCC1=CC=CC=C1)=O)C)C1=CC(=C(C=C1)O)I)=O)C)=O)C(=O)OC)B(O)O RWKOSHFCGWENBL-UBVMKEEMSA-N 0.000 description 2
- NWQWAJKFAUKDCZ-KYLFUZKPSA-N [5-[(2S)-2-[[(2S)-2-aminopropanoyl]amino]-3-methoxy-3-oxopropyl]-2-phenylmethoxyphenyl]boronic acid hydrochloride Chemical compound Cl.N[C@H](C(=O)N[C@@H](CC=1C=CC(=C(C=1)B(O)O)OCC1=CC=CC=C1)C(=O)OC)C NWQWAJKFAUKDCZ-KYLFUZKPSA-N 0.000 description 2
- 239000012445 acidic reagent Substances 0.000 description 2
- 235000004279 alanine Nutrition 0.000 description 2
- 125000003158 alcohol group Chemical group 0.000 description 2
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 2
- 125000000278 alkyl amino alkyl group Chemical group 0.000 description 2
- 125000003282 alkyl amino group Chemical group 0.000 description 2
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 2
- 125000000304 alkynyl group Chemical group 0.000 description 2
- 125000003368 amide group Chemical group 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
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- 239000008346 aqueous phase Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 206010003246 arthritis Diseases 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
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- 230000002209 hydrophobic effect Effects 0.000 description 1
- 125000001165 hydrophobic group Chemical group 0.000 description 1
- ORTFAQDWJHRMNX-UHFFFAOYSA-N hydroxidooxidocarbon(.) Chemical group O[C]=O ORTFAQDWJHRMNX-UHFFFAOYSA-N 0.000 description 1
- 125000005113 hydroxyalkoxy group Chemical group 0.000 description 1
- 125000005191 hydroxyalkylamino group Chemical group 0.000 description 1
- 125000005181 hydroxyalkylaminoalkyl group Chemical group 0.000 description 1
- 125000005182 hydroxyalkylcarbonyl group Chemical group 0.000 description 1
- 125000005350 hydroxycycloalkyl group Chemical group 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- COTNUBDHGSIOTA-UHFFFAOYSA-N meoh methanol Chemical compound OC.OC COTNUBDHGSIOTA-UHFFFAOYSA-N 0.000 description 1
- 229910000000 metal hydroxide Inorganic materials 0.000 description 1
- 150000004692 metal hydroxides Chemical class 0.000 description 1
- JGPSPXHPKGUYJV-GWCFXTLKSA-N methyl (2S)-3-(4-hydroxy-3-iodophenyl)-2-[[(2S)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoyl]amino]propanoate Chemical compound C(C)(C)(C)OC(=O)N[C@H](C(=O)N[C@H](C(=O)OC)CC1=CC(=C(C=C1)O)I)C JGPSPXHPKGUYJV-GWCFXTLKSA-N 0.000 description 1
- GHZZZPHSFHDSMY-JXFKEZNVSA-N methyl (2s)-3-(3-iodo-4-phenylmethoxyphenyl)-2-[[(2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoyl]amino]propanoate Chemical compound IC1=CC(C[C@@H](C(=O)OC)NC(=O)[C@H](C)NC(=O)OC(C)(C)C)=CC=C1OCC1=CC=CC=C1 GHZZZPHSFHDSMY-JXFKEZNVSA-N 0.000 description 1
- RUZLIIJDZBWWSA-INIZCTEOSA-N methyl 2-[[(1s)-1-(7-methyl-2-morpholin-4-yl-4-oxopyrido[1,2-a]pyrimidin-9-yl)ethyl]amino]benzoate Chemical group COC(=O)C1=CC=CC=C1N[C@@H](C)C1=CC(C)=CN2C(=O)C=C(N3CCOCC3)N=C12 RUZLIIJDZBWWSA-INIZCTEOSA-N 0.000 description 1
- 125000006533 methyl amino methyl group Chemical group [H]N(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- PEECTLLHENGOKU-UHFFFAOYSA-N n,n-dimethylpyridin-4-amine Chemical compound CN(C)C1=CC=NC=C1.CN(C)C1=CC=NC=C1 PEECTLLHENGOKU-UHFFFAOYSA-N 0.000 description 1
- WOOWBQQQJXZGIE-UHFFFAOYSA-N n-ethyl-n-propan-2-ylpropan-2-amine Chemical compound CCN(C(C)C)C(C)C.CCN(C(C)C)C(C)C WOOWBQQQJXZGIE-UHFFFAOYSA-N 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- PSACHCMMPFMFAJ-UHFFFAOYSA-N nmm n-methylmorpholine Chemical compound CN1CCOCC1.CN1CCOCC1 PSACHCMMPFMFAJ-UHFFFAOYSA-N 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000962 organic group Chemical group 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000005010 perfluoroalkyl group Chemical group 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- 125000003884 phenylalkyl group Chemical group 0.000 description 1
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 201000001223 septic arthritis Diseases 0.000 description 1
- 201000005671 spondyloarthropathy Diseases 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000005297 thienyloxy group Chemical group S1C(=CC=C1)O* 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- ZBZJXHCVGLJWFG-UHFFFAOYSA-N trichloromethyl(.) Chemical compound Cl[C](Cl)Cl ZBZJXHCVGLJWFG-UHFFFAOYSA-N 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 108010087967 type I signal peptidase Proteins 0.000 description 1
- 125000005500 uronium group Chemical group 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D245/00—Heterocyclic compounds containing rings of more than seven members having two nitrogen atoms as the only ring hetero atoms
- C07D245/02—Heterocyclic compounds containing rings of more than seven members having two nitrogen atoms as the only ring hetero atoms not condensed with other rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/06—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents
- C07K1/061—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents using protecting groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/64—Cyclic peptides containing only normal peptide links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Oncology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Communicable Diseases (AREA)
- General Chemical & Material Sciences (AREA)
- Analytical Chemistry (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Methods for making an arylomycin ring of formula t
4
R9O HO 5
R1 I R 7
R 2 R 3 R 6 (R) R
O HN
Pg -- A N -, O O
5or salts or solvates thereof, wherein R, R', R2, R', R4, RI, R6, R7, R', R9, RS, R'O and Pg' are as defined herein.
Description
This application is a divisional of Australian Patent Application No. 2018243724, filed on 26 March 2018, and is related to International Patent Application No. PCT/US2018/024351, filed on 26 March 2018, and claims priority to U.S. Provisional Application No. 62/477,268 filed on 27 March 2017, the disclosure of which is incorporated herein by reference.
BACKGROUND OF THE INVENTION Antibiotic resistance is a serious and growing phenomenon in contemporary medicine and has emerged as a major public health concern of the 21st century. Arylomycin-like compounds have been identified as inhibitors of bacterial signal peptidases and show potential for treatment of infection involving gram-positive and gram-negative bacterials strains that are resistant to existing antibiotics. Synthesis of new arylomycin analogs and in particular preparation of the ring portion of arylomycin, is difficult however. There is accordingly a need for new synthetic procedures for arylomycin analogs and the ring portion thereof
SUMMARY OF THE INVENTION The invention provides methods for making the arylomycin ring and variants thereof, and for making arylomycin analogs from the ring. In one aspect, the invention provides a method for making an arylomycin ring of formula o
4 5 Pg2 O1 5 OH R1 O R7
R2 R3 R6 (R) R 20~~ whren HN
wherein: Y is halogen; R is: hydrogen; or C1.4alkyl; and may be the same or different on each occurrence, or two R groups may form a C2 -6 alkylene that, together with the atoms to which they are attached, may form a five- or six membered ring; R 1, R 2, R3 , R4 , R 5 and R 6 each independently is: hydrogen; C1.4alkyl; halo-CI1 4alkyl; halo; amino; amino-CI 4 alkyl; hydroxy; hydroxy-C1. 6alkyl; cyano; cyano-C1Ialkyl; or nitro, wherein the amino and hydroxyl moieties may optionally include a protecting group; R? is: hydrogen; or C1. 4 alkyl;
R8 is: hydrogen; Ci 4 alkyl; halo-Ci-4 alkyl; halo; amino; amino-Ci4alkyl; hydroxy; hydroxy-C
6alkyl; cyan; or cyano-Ci 6alkyl, wherein the amino and hydroxyl moieties may optionally include a protecting group; Pg' is an optional amine protecting group; and Pg2 is an optional hydroxyl protecting group;
the method comprising:
reacting a phenyl boronate compound of formula n_: 2 4 lj9 O 5
RO-'B 7
OR R6 OR HN HCI H 2 N O 0
R8 or a salt or solvate thereof,
with a phenyl halide compound of formula e; OH R1 Y
R2 R3 NN OH
Pgi 0
or a salt or solvate thereof,
to form a compound of formula n;
OH RO'B'OR Y R6 OPg 2 R1
H R 5 R2 / R3 R R7 R4
P N N ROR Me 0 R H O or a salt or solvate thereof; and Eating the compound of formula n with chloro(crotyl)(tri-tert-butylphosphine)palladium(II), to make the compound of formula o; or a salt or solvate thereof.
In another embodiment, the invention provides a method of making an arylomycin ring of formula
2 4 Pg 05 OH0
R1 1 6 R7 R 2 R (R) R HN (S) H N (S) N 0O Pg1 0 R8
wherein Y, R, R', R2, R3 , R4,R, R, R 7, R, Pg and Pg 2 are as defined herein; the method comprising: reacting a phenyl boronate compound of formula m: 2 4 F 9 05
OR R6 OR HN H2N O O
R8 M or a salt or solvate thereof, with a phenyl halide compound of formula e; OH R1 Y
R2 R3
N OH Pgi 0 e or a salt or solvate thereof, in the presence of chloro(crotyl)(tri-tert-butylphosphine)palladium(II), to form a compound of formula y; Pg 2 4 1 RO OH O
R1 (R) 8
R2 / RR R7 NH 2
N Os) O IPgiO or a salt or solvate thereof; and cyclizing compound v by forming an amide bond to make the the compound o; or a salt or solvate thereof. The subject methods provide unexpectedly better overall yield in producing the ring compound n as well as improved chiral purity via avoidance of potential racemization events. Additional embodiments and details are provided below.
DETAILED DESCRIPTION OF THE INVENTION Definitions As used in the specification and the appended claims, the singular forms "a," "an" and "the" include plural referents unless the context clearly dictates otherwise. The term "about" as used herein, when referring to a numerical value or range, allows for a degree of variability in the value or range, for example, within 10%, or within 5% of a stated value or of a stated limit of a range. All percent compositions are given as weight-percentages, unless otherwise stated. All average molecular weights of polymers are weight-average molecular weights, unless otherwise specified. As used herein, "Alkyl" means the monovalent linear or branched saturated hydrocarbon moiety, consisting solely of carbon and hydrogen atoms, having from one to twelve carbon atoms. "Lower alkyl" refers to an alkyl group of one to six carbon atoms, i.e. C1-Calkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, and the like. "Alkenyl" means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms, containing at least one double bond, e.g., ethenyl, propenyl, and the like. "Alkynyl" means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms, containing at least one triple bond, e.g., ethynyl, propynyl, and the like. "Alkylene" means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms, e.g., methylene, ethylene, 2,2-dimethylethylene, propylene, 2-methylpropylene, butylene, pentylene, and the like. "Alkoxy" and "alkyloxy", which may be used interchangeably, mean a moiety of the formula -OR, wherein R is an alkyl moiety as defined herein. Examples of alkoxy moieties include, but are not limited to, methoxy, ethoxy, isopropoxy, and the like. "Alkoxyalkyl" means a moiety of the formula Ra-O-Rb-, where Ra is alkyl and R is alkylene as defined herein. Exemplary alkoxyalkyl groups include, by way of example, 2-methoxyethyl, 3-methoxypropyl, 1-methyl-2-methoxyethyl, 1-(2-methoxyethyl)-3-methoxypropyl, and 1-(2 methoxyethyl)-3-methoxypropyl. "Alkoxyalkoxy' means a group of the formula -O-R-R' wherein R is alkylene and R' is alkoxy as defined herein. "Alkylcarbonyl" means a moiety of the formula -C(O)-R, wherein R is alkyl as defined herein. "Alkoxycarbonyl" means a group of the formula -C(O)-R wherein R is alkoxy as defined herein.
"Alkylcarbonylamino" means a group of the formula -R-C(O)-NR'- wherein R is alkyl and R' is hydrogen or alkyl. "Alkylcarbonylalkyl" means a group of the formula -R-C(O)-R' wherein R is alkylene and R' is alkyl as defined herein. "Alkoxyalkylcarbonyl" means a moiety of the formula -C(O)-R-R', wherein R is alkylene and R' is alkoxy as defined herein. "Alkoxycarbonylalkyl" means a group of the formula -R-C(O)-R' wherein R is alkylene and R' is alkoxy as defined herein. "Alkoxycarbonylamino" means a moiety of the formula R-C(O)-NR'-, wherein R is alkoxy and R' is hydrogen or alkyl as defined herein. "Alkoxycarbonylaminoalkyl" means a moiety of the formula R-C(O)-NR'-R"-, wherein R is alkoxy, R' is hydrogen or alkyl, and R" is alkylene as defined herein. "Alkoxycarbonylalkoxy"means a group of the formula -O-R-C(O)-R' wherein R is alkylene and R' is alkoxy as defined herein. "Hydroxycarbonylalkoxy" means a group of the formula -O-R-C(O)-OH wherein R is alkylene as defined herein. "Alkylaminocarbonylalkoxy" means a group of the formula -O-R-C(O)-NHR' wherein R is alkylene and R' is alkyl as defined herein. "Dialkylaminocarbonylalkoxy" means a group of the formula -O-R-C(O)-NR'R" wherein R is alkylene and R' and R" are alkyl as defined herein. "Alkylaminoalkoxy" means a group of the formula -O-R-NHR' wherein R is alkylene and R' is alkyl as defined herein. "Dialkylaminoalkoxy" means a group of the formula -O-R-NR'R' wherein R is alkylene and R' and R" are alkyl as defined herein. "Alkylsulfonyl" means a moiety of the formula - S0 2-R, wherein R is alkyl as defined herein. "Alkylsulfonylalkyl means a moiety of the formula -R'-S0 2-R" where where R' is alkylene and R" is alkyl as defined herein. "Alkylsulfonylalkoxy" means a group of the formula -O-R-S02-R' wherein R is alkylene and R' is alkyl as defined herein. "Amino means a moiety of the formula -NRR'wherein R and R' each independently is hyrdogen or alkyl as defined herein. "Amino thus includes "alkylamino (where one of R and R' is alkyl and the other is hydrogen) and "dialkylamino (where R and R' are both alkyl. "Aminocarbonyl" means a group of the formula -C(O)-R wherein R is amino as defined herein. "N-hydroxy-aminocarbonyl" means a group of the formula -C(O)-NR-OH wherein R is hydrogen or alkyl as defined herein. "N-alkoxy-aminocarbonyl" means a group of the formula -C(O)-NR-R' wherein R is hydrogen or alkyl and R' is alkoxy as defined herein.
"Aminocarbonylaminoalkyl" means a group of the formula R 2N-C(O)-NR'-R"- wherein each R is independently hydrogen or alkyl, R' is hydrogen or alkyl, and R" is alkylene as defined herein.
"N-alkyl-aminocarbonyl means a group of the formula -C(O)-NH-R wherein R is alkyl as defined herein.
"N-hydroxy-N-alkylaminocarbonylmeans a group of the formula -C(O)-NRR' wherein R is alkyl as defined herein and R' is hydroxy.
"N-alkoxy-N-alkylaminocarbonyl" means a group of the formula -C(O)-NRR' wherein R is alkyl and R' is alkoxy as defined herein. "N,N-di-CI 6 alkyl-aminocarbonyl" means a group of the formula -C(O)-NRR' wherein R and R'
are alkyl as defined herein. "Aminosulfonyl" means a group of the formula -S0 2-NH 2
. "N-alkylaminosulfonyl" means a group of the formula -S0 2 -NHR wherein R is alkyl as defined herein. "N,N-dialkylaminosulfonyl" means a group of the formula -S02 -NRR' wherein R and R' are alkyl
as defined herein.
"Alkylsulfonylamino" means a group of the formula -NR'-S02-R wherein R id alkyl and R' is hydrogen or alkyl as defined herein. "N-(alkylsulfonyl)-aminoalkyl" means a group of the formula -R-NH-S0 2 -R' wherein R is
alkylene and R' is alkyl as defined herein. "N-(Alkylsulfonyl)aminocarbonyl" means a group of the formula -C(O)-NH-SO 2 -R wherein
wherein R is alkyl as defined herein. "N-(Alkylsulfonyl)-N-alkylaminocarbonyl" means a group of the formula -C(O)-NR-SO 2 -R' wherein wherein R and R' are alkyl as defined herein.
"N-Alkoxyalkyl-aminocarbonyl" means a group of the formula -C(O)-NR-R'-OR" wherein R is
hydrogen or alkyl, R' is alkylene, and R" is alkyl as defined herein. "N-Hydroxyalkyl-aminocarbonyl" means a group of the formula -C(O)-NR-R'-OH" wherein R is hydrogen or alkyl and R' is alkylene as defined herein.
"Alkoxyamino" means a moiety of the formula -NR-OR'wherein R is hydrogen or alkyl and R'is alkyl as defined herein.
"Alkylsulfanyl" means a moiety of the formula -SR wherein R is alkyl as defined herein. "Aminoalkyl" means a group -R-R'wherein R'is amino and R is alkylene as defined herein. "Aminoalkyl" includes aminomethyl, aminoethyl, 1-aminopropyl, 2-aminopropyl, and the like.
The amino moiety of "aminoalkyl" may be substituted once or twice with alkyl to provide "alkylaminoalkyl" and "dialkylaminoalkyl" respectively. "Alkylaminoalkyl" includes methylaminomethyl, methylaminoethyl, methylaminopropyl, ethylaminoethyl and the like. "Dialkylaminoalkyl" includes dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl, N-methyl-N-ethylaminoethyl, and the
like. "Aminoalkoxy" means a group -OR-R'wherein R'is amino and R is alkylene as defined herein.
"Alkylsulfonylamido" means a moiety of the formula -NR'S02 -R wherein R is alkyl and R' is hydrogen or alkyl.
"Aminocarbonyloxyalkyl" or "carbamylalkyl" means a group of the formula -R-0-C(O)-NR'R" wherein R is alkylene and R', R" each independently is hydrogen or alkyl as defined herein.
"Alkynylalkoxy" means a group of the formula -O-R-R'wherein R is alkylene and R'is alkynyl as defined herein.
"Aryl" means a monovalent cyclic aromatic hydrocarbon moiety consisting of a mono-, bi- or tricyclic aromatic ring. The aryl group can be optionally substituted as defined herein. Examples of aryl moieties include, but are notlimited to, phenyl, naphthyl, phenanthryl, fluorenyl, indenyl, pentalenyl,
azulenyl, oxydiphenyl, biphenyl, methylenediphenyl, aminodiphenyl, diphenylsulfidyl, diphenylsulfonyl, diphenylisopropylidenyl, benzodioxanyl, benzofuranyl, benzodioxylyl, benzopyranyl, benzoxazinyl,
benzoxazinonyl, benzopiperadinyl, benzopiperazinyl, benzopyrrolidinyl, benzomorpholinyl, methylenedioxyphenyl, ethylenedioxyphenyl, and the like, of which may be optionally substituted as defined herein.
"Arylalkyl" and "Aralkyl", which may be used interchangeably, mean a radical-RaRb where Ra is an alkylene group and Rb is an aryl group as defined herein; e.g., phenylalkyls such as benzyl, phenylethyl, 3-(3-chlorophenyl)-2-methylpentyl, and the like are examples of arylalkyl. "Arylsulfonyl means a group of the formula -S0 2-R wherein R is aryl as defined herein.
"Aryloxy" means a group of the formula -O-R wherein R is aryl as defined herein. "Aralkyloxy" means a group of the formula -O-R-R" wherein R is alkylene and R'is aryl as
defined herein. "Carboxy" or "hydroxycarbonyl", which may be used interchangeably, means a group of the formula -C(O)-OH. "Cyanoalkyl" " means a moiety of the formula -R'-R", where R' is alkylene as defined herein and
R" is cyano or nitrile. "Cycloalkyl" means a monovalent saturated carbocyclic moiety consisting of mono- or bicyclic rings. Particular cycloalkyl are unsubstituted or substituted with alkyl. Cycloalkyl can optionally be
substituted as defined herein. Unless defined otherwise, cycloalkyl may be optionally substitued with one or more substituents, wherein each substituent is independently hydroxy, alkyl, alkoxy, halo, haloalkyl,
amino, monoalkylamino, or dialkylamino. Examples of cycloalkyl moieties include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like, including partially unsaturated (cycloalkenyl) derivatives thereof.
"Cycloalkenyl" means a cycloalkyl as defined herein that includes at least one double bond or
unsaturation. Exemplary cycloalkenyl include cyclohexenyl, cyclopentenyl, cyclobutenyl and the like.
"Cycloalkylalkyl" means a moiety of the formula -R'-R", where R' is alkylene and R" is cycloalkyl as defined herein.
"Cycloalkylalkoxy" means a group of the formula -O-R-R' wherein R is alkylene and R' is cycloalkyl as defined herein.
"Cycloalkylcarbonyl" means a moiety of the formula -C(O)-R, wherein R is cycloalkyl as defined herein. "C3-6cycloalkyl-C1.alkyl-carbonyl" means a moiety of the formula -C(O)-R, wherein R is
cycloalkylalkyl as defined herein.
"Cyanoalkylcarbonyl" means a moiety of the formula -C(O)-R-R', wherein R is alkylene as defined herein and R' is cyano or nitrile.
"N-Cyano-aminocarbonyl" means a moiety of the formula -C(O)-NHR, wherein R is cyano or nitrile. "N-Cyano-N-alkyl-aminocarbonyl" means a moiety of the formula -C(O)-NRR'-R, wherein R' is
alkyl as defined herein and R is cyano or nitrile. "Cycloalkylsulfonyl" means a group of the formula -S0 2 -R wherein R is cycloalkyl as defined
herein. "Cycloalkylalkylsulfonyl" means a group of the formula -S0 2 -R wherein R is cycloalkylalkyl as
defined herein.
"Formyl" means a moiety of the formula -C(O)-H. "Heteroaryl" means a monocyclic or bicyclic radical of 5 to 12 ring atoms having at least one aromatic ring containing one, two, or three ring heteroatoms selected from N, 0, or S, the remaining ring atoms being C, with the understanding that the attachment point of the heteroaryl radical will be on an
aromatic ring. The heteroaryl ring may be optionally substituted as defined herein. Examples of heteroaryl moieties include, but are notlimited to, optionally substituted imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, thienyl, benzothienyl, thiophenyl, furanyl, pyranyl, pyridyl, pyrrolyl, pyrazolyl, pyrimidyl, quinolinyl, isoquinolinyl, benzofuryl, benzothiophenyl, benzothiopyranyl, benzimidazolyl, benzooxazolyl, benzooxadiazolyl, benzothiazolyl, benzothiadiazolyl,
benzopyranyl, indolyl, isoindolyl, triazolyl, triazinyl, quinoxalinyl, purinyl, quinazolinyl, quinolizinyl,
naphthyridinyl, pteridinyl, carbazolyl, azepinyl, diazepinyl, acridinyl and the like, each of which may be optionally substituted as defined herein. Heteroarylalkyl" or "heteroaralkyl" means a group of the formula -R-R'wherein R is alkylene and
R' is heteroaryl as defined herein. "Heteroarylsulfonyl means a group of the formula -S0 2 -R wherein R is heteroaryl as defined
herein. "Heteroaryloxy" means a group of the formula -0-R wherein R is heteroaryl as defined herein.
"Heteroarylcarbonyl" means a group of the formula -C(O)-R wherein R is heteroaryl as defined
herein. "Heteroaralkyloxy" means a group of the formula -O-R-R" wherein R is alkylene and R' is
heteroaryl as defined herein. The terms "halo", "halogen" and "halide", which may be used interchangeably, refer to a
substituent fluoro, chloro, bromo, or iodo.
"Haloalkyl" means alkyl as defined herein in which one or more hydrogen has been replaced with same or different halogen. Exemplary haloalkyls include -CH 2Cl,
-CH 2CF3, -CH 2 CCl3 , perfluoroalkyl (e.g., -CF 3), and the like. "Haloalkoxy" means a moiety of the formula -OR, wherein R is a haloalkyl moiety as defined herein. An exemplary haloalkoxy is difluoromethoxy. "Heterocycloamino" means a saturated ring wherein at least one ring atom is N, NH or N-alkyl and the remaining ring atoms form an alkylene group. "Heterocyclyl" means a monovalent saturated moiety, consisting of one to three rings, incorporating one, two, or three or four heteroatoms (chosen from nitrogen, oxygen or sulfur). The heterocyclyl ring may be optionally substituted as defined herein. Examples of heterocyclyl moieties include, but are notlimited to, optionally substituted piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azepinyl, pyrrolidinyl, azetidinyl, tetrahydropyranyl, tetrahydrofuranyl, oxetanyl and the like. Such heterocyclyl may be optionally substituted as defined herein. "Heterocyclylalkyl" means a moiety of the formula -R-R'wherein R is alkylene and R'is heterocyclyl as defined herein. "Heterocyclyloxy" means a moiety of the formula -OR wherein R is heterocyclyl as defined herein. "Heterocyclylalkoxy" means a moiety of the formula -OR-R'wherein R is alkylene and R' is heterocyclyl as defined herein. "Hydroxyalkoxy" means a moiety of the formula -OR wherein R is hydroxyalkyl as defined herein. "Hydroxyalkylamino" means a moiety of the formula -NR-R'wherein R is hydrogen or alkyl and R' is hydroxyalkyl as defined herein. "Hydroxyalkylaminoalkyl" means a moiety of the formula -R-NR'-R" wherein R is alkylene, R'is hydrogen or alkyl, and R" is hydroxyalkyl as defined herein. "Hydroxycarbonylalkyl" or "carboxyalkyl" means a group of the formula -R-(CO)-OH where R is alkylene as defined herein. "Hydroxycarbonylalkoxy" means a group of the formula -O-R-C(O)-OH wherein R is alkylene as defined herein. "Hydroxyalkylcarbonyl" means a moiety of the formula -C(O)-R-R', wherein R is alkylene as defined herein and R' is hydroxy. "Hydroxyalkyloxycarbonylalkyl" or "hydroxyalkoxycarbonylalkyl" means a group of the formula -R-C(O)-O-R-OH wherein each R is alkylene and may be the same or different. "Hydroxyalkyl" means an alkyl moiety as defined herein, substituted with one or more, for example, one, two or three hydroxy groups, provided that the same carbon atom does not carry more than one hydroxy group. Representative examples include, but are notlimited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 2-hydroxy-1-hydroxymethylethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2-(hydroxymethyl)-3-hydroxypropyl
"Hydroxycycloalkyl" means a cycloalkyl moiety as defined herein wherein one, two or three hydrogen atoms in the cycloalkyl radical have been replaced with a hydroxy substituent. Representative
examples include, but are not limited to, 2-, 3-, or 4-hydroxycyclohexyl, and the like. "Oxo" means a group of the formula =0 (i.e., an oxygen with a double bond). Thus, for example, a 1-oxo-ethyl group is an acetyl group.
"Alkoxy hydroxyalkyl" and "hydroxy alkoxyalkyl", which may be used interchangeably, means
an alkyl as defined herein that is substituted at least once with hydroxy and at least once with alkoxy. "Alkoxy hydroxyalkyl" and "hydroxy alkoxyalkyl" thus encompass, for example, 2-hydroxy-3 methoxy-propan-1-yl and the like.
"Urea"or "ureido" means a group of the formula -NR'-C(O)-NR"R"' wherein R', R" and R"' each independently is hydrogen or alkyl.
"Carbamate" means a group of the formula -0-C(O)-NR'R" wherein R'and R" each independently is hydrogen or alkyl. "Carboxy" means a group of the formula -0-C(O)-OH.
"Sulfonamido" means a group of the formula -S0 2 -NR'R" wherein R', R" and R'" each independently is hydrogen or alkyl. "Optionally substituted" when used in association with an "aryl", phenyl", "heteroaryl" "cycloalkyl" or "heterocyclyl" moiety means that such moiety may be unsubstituted (i.e., all open
valencies are occupied by a hydrogen atom) or substituted with specific groups as related herein. "Leaving group" means the group with the meaning conventionally associated with it in synthetic
organic chemistry, i.e., an atom or group displaceable under substitution reaction conditions. Examples of leaving groups include, but are not limited to, halogen, alkane- or arylenesulfonyloxy, such as methanesulfonyloxy, ethanesulfonyloxy, thiomethyl, benzenesulfonyloxy, tosyloxy, and thienyloxy,
dihalophosphinoyloxy, optionally substituted benzyloxy, isopropyloxy, acyloxy, and the like.
"Modulator" means a molecule that interacts with a target. The interactions include, but are not limited to, agonist, antagonist, and the like, as defined herein. "Optional" or "optionally" means that the subsequently described event or circumstance may but
need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not.
"Disease" and "Disease state" means any disease, condition, symptom, disorder or indication. "Inert organic solvent" or "inert solvent" means the solvent is inert under the conditions of the reaction being described in conjunction therewith, including for example, benzene, toluene, acetonitrile,
tetrahydrofuran, N,N-dimethylformamide, chloroform, methylene chloride or dichloromethane,
dichloroethane, diethyl ether, ethyl acetate, acetone, methyl ethyl ketone, methanol, ethanol, propanol, isopropanol, tert-butanol, dioxane, pyridine, and the like. Unless specified to the contrary, the solvents used in the reactions of the present invention are inert solvents.
"Pharmaceutically acceptable" means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary as well as human pharmaceutical use. "Pharmaceutically acceptable salts" of a compound means salts that are pharmaceutically acceptable, as defined herein, and that possess the desired pharmacological activity of the parent compound. It should be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs) as defined herein, of the same acid addition salt. "Protective group" or "protecting group" means the group which selectively blocks one reactive site in a multifunctional compound such that a chemical reaction can be carried out selectively at another unprotected reactive site in the meaning conventionally associated with it in synthetic chemistry. Certain processes of this invention rely upon the protective groups to block reactive nitrogen and/or oxygen atoms present in the reactants. For example, the terms "amino-protecting group" and "nitrogen protecting group" are used interchangeably herein and refer to those organic groups intended to protect the nitrogen atom against undesirable reactions during synthetic procedures. Exemplary nitrogen protecting groups include, but are not limited to, trifluoroacetyl, acetamido, benzyl (Bn), benzyloxycarbonyl (carbobenzyloxy, CBZ), p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, tert-butoxycarbonyl (BOC), and the like. The artisan in the art will know how to chose a group for the ease of removal and for the ability to withstand the following reactions. "Solvates" means solvent additions forms that contain either stoichiometric or non stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate, when the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one of the substances in which the water retains its molecular state as H 20, such combination being able to form one or more hydrate. "Arthritis" means a disease or condition that causes damage to joints of the body and pain associated with such joint damage. Arthritis includes rheumatoid arthritis, osteoarthritis, psoriatic arthritis, septic arthritis, spondyloarthropathies, gouty arthritis, systemic lupus erythematosus and juvenile arthritis, osteoarthritis, and other arthritic conditions. "Respiratory disorder" refers to, without limitation, chronic obstructive pulmonary disease (COPD), asthma, bronchospasm, and the like. "Subject" means mammals and non-mammals. Mammals means any member of the mammalia class including, but not limited to, humans; non-human primates such as chimpanzees and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, and swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice, and guinea pigs; and the like. Examples of non-mammals include, but are not limited to, birds, and the like. The term "subject" does not denote a particular age or sex.
"Therapeutically effective amount" means an amount of a compound that, when administered to a subject for treating a disease state, is sufficient to effect such treatment for the disease state. The "therapeutically effective amount" will vary depending on the compound, disease state being treated, the severity or the disease treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending medical or veterinary practitioner, and other factors. The terms "those defined above" and "those defined herein" when referring to a variable incorporates by reference the broad definition of the variable as well as particular definitions, if any. "Treating" or "treatment" of a disease state includes, inter alia, inhibiting the disease state, i.e., arresting the development of the disease state or its clinical symptoms, and/or relieving the disease state
, i.e., causing temporary or permanent regression of the disease state or its clinical symptoms. The terms "treating", "contacting" and "reacting" when referring to a chemical reaction means adding or mixing two or more reagents under appropriate conditions to produce the indicated and/or the desired product. It should be appreciated that the reaction which produces the indicated and/or the desired product may not necessarily result directly from the combination of two reagents which were initially added, i.e., there may be one or more intermediates which are produced in the mixture which ultimately leads to the formation of the indicated and/or the desired product. The invention provides and methods for making the ring portion of arylomycin, and hence methods for making arylomycin analogs, with unexpectedely improved yields and improved chiral purity. The subject methods utilize the palladium catalyst chloro(crotyl)(tri-tert-butylphosphine)palladium(II), also known as "Pd162," in a Suzuki coupling reaction to make the arylomycin ring in high overall yield. Pd162 has the structure:
CI -Pd -- t-Bu t-Bu \t-Bu
Pd162 is commercially available from Johnson Matthey Fine Chemicals and other sources, and may be prepared according to the procedure reported by DeAnglis et al., J.Org.Chem.Vol. 80, pp 6794-6813 (2015). Use of Pd162-based coupling in accordance with the invention results in yields of about 85% in an important step in the formation of the arylomycin ring. Amide coupling reactions are utilized in many of the synthetic procedures described herein and the reagents involved can be used interchangeably in many instances. Amide coupling as described herein may in many embodiments utilize carbodiimide reagents such as dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC) and ethyl-(N',N'-dimethylamino)propylcarbodiimide hydrochloride (EDC or EDCI). 1-Hydroxybenzotriazole (HOBt) or 1-hydroxy-7-azabenzotriazole (HOAt) may be used with carbodiimide based coupling reactions to mimize racemization.. In other embodiments additional reagents that may be used for amide coupling, include (Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), (Benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate
(PyBOP), (7-Azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP) and Bromotripyrrolidinophosphonium hexafluorophosphate (PyBrOP). In still other embodiments amide coupling reagents usable with the invention includeO-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) and O-(Benzotriazol-l-yl)- N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU),O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluroniumhexafluorophosphate(HATU), 0 (7-Azabenzotriazol-1-yl)- N,N,N',N'-tetramethyluronium tetrafluoroborate (TATU), 0-(6 Chlorobenzotriazol-1-yl)-N,N,N',N'-tetramethyluroniumhexafluorophosphate (HCTU), 0-(N-Suc cinimidyl)-1,1,3,3-tetramethyl-uronium tetrafluoroborate (TSTU), 0-(5-Norbornene-2,3-dicarboximido) N,N,N',N'-tetramethyluronium tetrafluoroborate (TNTU) and0-(1,2-Dihydro-2-oxo-1-pyridyl N,N,N',N'-tetramethyluronium tetrafluoroborate (TPTU), 3-(Diethylphosphoryloxy)-1,2,3-benzotriazin 4(3H)-one (DEPBT), isobutyl chloroformate (IBCF), and 6-chloro-2,4-dimethoxy-s-triazine (CDMT). Specific examples disclosed herein utilize some of the above amide coupling reagents, but it should be understood that many of the above amide compling reagents may alternatively be used. The subject methods will be more fully understood with reference to the several reaction schemes below, wherein: R is: hydrogen; or C14alkyl; and may be the same or different on each occurrence; R 1, R 2, R 3, R4,R 5 and R e ach independently is: hydrogen; C1 .4alkyl; halo-C1 .4alkyl; halo; amino; amino-C 1 4alkyl; hydroxy; hydroxy-C1.6alkyl; cyano; cyano-C1.alkyl; or nitro, wherein the amino and hydroxyl moieties each may optionally include a protecting group; R7 is: hydrogen; or C1. 4alkyl; R' is: hydrogen; C14alkyl; halo-C1 4 alkyl; halo; amino; amino-C1.4alkyl; hydroxy; hydroxy-Ci1 6alkyl; cyano; or cyano-C -16alkyl, wherein the amino and hydroxyl moieties may optionally include a protecting group; R9 is: C1 .4alkyl; halo-C1 .4alky; hydroxyl-C1 .4alkyl; amino-C1 .4alkyl, aminosulfonyl-C1 4 alkyl; or C1. 4alkoxy-C14alkyl, wherein the amino and hydroxyl moieties each may optionally include a protecting group; R10 is: hydroxyl-C1 4 alkyl; amino-C1 - 4alkyl; aminosulfonyl-C1 4 alkyl; or C 1 - 4 alkoxy-C1 - 4 alkyl,
wherein the amino and hydroxyl moieties each may optionally include a protecting group; Ra is: hydrogen; or C 1 .4alkyl; and may be the same or different on each occurrence, or two R groups may form a C2-6alkylene that, together with the atoms to which they are attached, may form a five or six-membered ring; X is a leaving group; Y is halogen (fluoro, chloro, bromo or iodo); Pg 1 is an optional amine protecting group and may be the same or different in each occurence; Pg2 is an optional hydroxyl protecting group and may be the same or different in each occurence; TG is a "tail group" and is defined further herein; and WG is a "warhead group" and is defined further herein.
Protecting groups are shown generically in several of the reaction schemes herein, and those skilled in the art will recognize that various different protection and deprotection schemes can in many instances be used alternatively, as described in "Greene's Protective Groups in Organic Synthesis," Fifth Edition, 2014 by John Wiley& Sons, Inc. In some instances amine or hydroxyl substituents may present in the variables R 1 through R 10 described herein, and it should be understood that suitable protecting groups may be utilized in association with such substituents. OH OH OH RR1 Y R1 Y R1 halogenation N-protection
R Step R2 R3 Step 2 R2 R3 OH OH Pg I OH H 2N H2N bN O H oc OH OH R1 Y trioxane Reduce 1 2 3 R2 R3 2 R Step 3 R Step 4 N OH gi'N 0 d Pgi O
Scheme 1A Referring now to Scheme 1A, synthesis of an intermediate halodophenol compound e is shown. In step 1 of Scheme 1A, phenol aminoacid compound a undergoes halogenation to afford halophenol aminoacid compound b. halogenation of step 1 may be carried out using F12 , Cl 2, Br 2 or12 in aqueous ammonia solution at reduced temperature. In many embodiments 12 is used in this step. In step 2, an amine protecting group may be introduced to provide amine-protected halophenol aminoacid compound c. The protecting groups in many embodiments can be a carboxybenzyl (cbz) group, with the reaction of step 2 achieved using carboxybenzyl chloride with compound b under basic aqueous conditions. A ring formation is carried out in step 3 by reaction of compound c with trioxane to afford halophenol oxooxazoldine compound d. The reaction of step 3 may occur in polar aprotic solvent such as THF or methyl-THF and in the presence of tosylic acid. A reduction reaction is then carried out in step 4 to give N-methyl aminoacid intermediate compound e. The reaction of step 4 may be done using a hydrosilane reagent such as triethylsilane under acidic conditions using trifluoroacetic acid in polar aprotic solvent such as dichloromethane. Compound e may then be used as shown below in Scheme IC or ID.
4 4 4
HO HO halogenation HO HO 5 Ester formation HO
Step 1 N Step2 y RS R6 R (R OH (R) OH (R) OR H 2N fH 2N gH 2 Nh 2 4 4
H OH HO 55 00, 5 H ,,O HO ' i O-Protection I Pg' o R7 R7 6 R8 i R Step 4 R6 (R) OR (R) OR Step 3 H HN NH pg1-N 00 PgNH 0 k
2 PgF2 4 Pg 4 5O 5 ronate N-deprotect Formation OR R7R7 RaO B B Step 6 OR~~ RORORa Oa R (R) OR RHN OR NH- RH O 01 H 2N 00 p NH RRR Scheme lB Scheme lB illustrates the syntehsise of boronate intermediate compound j., wherein Y, R, R1 , R 2 R 3, R 4,R, R 6, R 7, R, Pg' and Pg 2 are as defined herein. In step 1 of Scheme iB, phenol aminoacid f is halogenated to give halophenol aminoacid compound g. As in the halogenation of Scheme lA, this reaction may utilize F12, Cl 3 , Br 2 or 12 as an halogenation reagent, and the reaction may be carried out in aqueous ammonia solution at reduced temperature. In step 2 the carboxylate group of compound g is optionally protected via esterification, to afford the corresponding ester compound h.. This esterification may be achieved using methanol (to form methyl ester) or other lower alcohol as solvent and in the presence of acid or acid chloride. An amide coupling is carried out in step 3 wherein optionally protected amino acid compound i is reacted with compound h to provide dipeptide compounds. Many different amide coupling reagents and conditions may be used in this step as noted above. In one embodiment the amide coupling of step 3 may be achieved utilizing 6-Chloro-2,4-dimethoxy-s-triazine (CDMT) in the presence of N-methyl morpholine in polar aprotic solvent such as dichloromethane. In certain embodiments the protected amino acid I may be Boc-protected alanine such that R' is (s)-methyl. In step 4 a hydroxyl protecting group is optionally introduced onto compound i to afford 0 protected compound k. In certain embodiments the protecting group may be benzyl and is provided by reaction of compound j with benzyl halide in polar aprotic solvent such as acetone, and optionally in the presence of a mild base such as potassium carbonate. A boronate ester is formed in step 5 by treatment of compound k with a boronating agen (not shown) t to yield boronate compound 1. In many embodiments the boronating agent may be pinacolborane or bis(pinacolato)diboron (4,4,5,5-Tetramethyl-1,3,2-dioxaborolane). This reaction is carried out in the presence of a palladium catalyst such as Pd(dppf)C12 in polar aprotic solvent such as DMSO. The boronate ester may optionally be hydrolyzed (not shown) to the corresponding boronic acid. Such hydrolysis may be effected using acid such as HCl in the presence of sodium periodate in polar aprotic solvent such as THF or methyl-THF. Amine deprotection optionally occurs in step 6 top remove the amine protecting group from conpound I to give compound m. In embodiments where the protecting groupis a a Boc group, the deprotection reaction may utilize HCl or other acid in methanol solvent. Compound m may be then be used as described in Scheme IC and ID below.
Scheme IC
Ffg2 4 R5 OH OH Ra BOR 1 6Op RIG R1 AMkjie R RaG.B + R Coup in1
ORaR6 R2 R3 Step 1 R3 R N OR OH H HCI H 2 N 0 OPg1O e Pg N N ROR
Re m Pg 2 4 Me 0 Rs H O 3 OH R (R) OR chloro(crotyl 7 (tri-tert-but Ihosphine) RR palladium(ii
Step 2 R2 R3RN- O
N 0 R Pg O 5
SchemeC illustratesthesyntehsis ofarylomycin ringcompoundowhereinR,RR 2 ,R 3 ,R 4,R, RR 7 ,RPgandPg 2 are as defined herein. In step 1 of Scheme IC, the phenyl halo N-methyl aminoacid compound e is reacted with boronate dipeptide compound m from Scheme IB, via an amide coupling reaction, to give tripeptide compound n. Many different amide coupling reagents and conditions may be used in this step, and in one embodiment the reaction is carried out using isobutyl chloroformate (IBCF) in the presence of N-methyl morpholine, in polar aprotic solvent such as DMF, THF, or a mixture thereof. In step 2, a Suzuki-type coupling reaction is carried out to effect a ring closure in compound n, in the presence of chloro(crotyl)(tri-tert-butylphosphine)palladium(II) ("Pd162"), and thus afford arylomycin ring compound o in accordance with the invention. The reaction of step 2 may be done in aqueous acetonitrile and in the presence of mild base such as potassium bicarbonate.
The reaction of step 2 occurs in high yield, and in many embodiments a yield of at least 60-70% under kilogram scale conditions, and in some embodiments 75% is achieved, and certain embodiments at least 80%, and in some embodiments 85%, which are substantially and unexpectedly better yields than has previously been achieved utilizing several different palladium catalysts under different conditions. Previously reported synthetic yields for arylomycin ring formation are substantially lower than are achieved by the present invention. For example, Dufour et al., Chem. Eur. J. 2010, 16, 10523-10534 reported yields ranging from 0-54% using multiple different Pd catalysts, and such yields have not been reproducible beyond benchtop scale reactions. Romesburg et al., J. Am. Chem. Soc., 2007. 129, 15830 15838 report yields of only 19-40% utilizing various different Pd catalysts and different solvent conditions and, again, the reported yields are not repeatable in larger scale reactions. The invention also unexpected provides chiral purity of >99%de. Fg 2 4
05 OH IR1 Y Rao 7 + chloro(crotyl) 2 R3 (tri-tert-butylphosphine) OROR N OH palladium(II) HN ORNN O H 2N 0 pg 1 0 e Step 1
R8
2 ~Pg 2 4 Pg2 41 1 5R O O0 OH 0OH 7~
R1 (R)N 8 6
3 R6 R7 NH 2 Step 2 R2 R H R (S) H 0 N (s) OH NN 0 O pg1 0 Pg 0 R8
Scheme ID Scheme ID demonstrates the synthesis of arylomycin ring compound o via an alternate route, wherein Y, R, R1 , R2 , R3 , R4 ,R, R6, R 7, R, Pg' and Pg 2 are as defined herein. In step 1, a Suzuki-type coupling reaction is used with compound m from Scheme 1B and compound e from Scheme 1A, in the presence of chloro(crotyl)(tri-tert-butylphosphine)palladium(II) ("Pd162"), to afford bispehnol compound x. The reaction of step 1 may be carried out in aqueous THF and in the presence of potassium phosphate. This reaction occurs in high yield, and in many embodiments a yield of at least 75% is achieved, and certain embodiments at least 80%, and in some embodiments 85%, which are substantially and unexpectedly better yields than has previously been achieved utilizing several different palladium catalysts under different conditions. For example, Romesburg et al., J. Am. Chem. Soc., 2007. 129, 15830-15838 reports a yield of 36% using PdC 2(dppf) in DMOS. The invention also unexpected provides chiral purity of >99%de.
In step 2 compound x undergoes cyclization via amide coupling to afford arylomycin ring compound o in accordance with the invention. The amide compling in certain embodiments may be done
in the presence of (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP) and N methyl morpholine in polar aprotic solvent such as DMF. Pg 2 4 Pg 2 4 4
S 9 R -X P RO 5 1. O-Deprotect R9 HO 5 OH 0 2. N-deprotect 0 R 7 0-alkylation R1 RR R.
Step Step 2 | R2 / (R) R R2 / 3 (R) R R2 / 3 R (R) R HN HN HN S(S) H 0 N) H S) H 0 N 0 0 N 0 N 0 r Igi O R8 Pg O R8 H O R8
Pg 1 o HN R9,. HO OH 0H 1. N-deprotect 10 R s R1 R 2. TG-COOH u Amide Coupling R Amide Coupling ' R2 R3 (R) R Step HN Step 4
PgI N s) t P9 R8 t Rio
4 4
RR9 O HO 5 1. Hydrolyse R9O HO 5 2. H 2N-WG w0 1 R7 Amide Coupling R1 R R 3 Step 5 R2 R 6 (R) R R 0 HN WG 0HN H TGN (s) O v N N 00 x 8 1 8 0 R10 0 R 0 Rio 0 R
Scheme 1E
Scheme 1E demonstrates the synthesis of arylomycin analog compounds w from ring compound o, wherein R, R1 , R 2 , R3 , R4 ,R5 , R 6, R 7 , R', R 9 , R 10, Pg' and Pg 2 are as defined herein. In step 1 of Scheme 1E, an optional0-alkylation occurs in which arylomycin ring compound o is
treated with alkylating agent p to afford0-alkylated compound -. In certain embodiments reagent p is an amino- Ci 4 alkyl halide wherein the amino includes a protecting group such as Boc. The alkylation
reaction may be carried out in dimethylacetamide or other polar aprotic solvent in the presence of potassium phosphate. This step may be omitted such that the phenolic hydroxyl groups of compound o are un-alkylated. Alternatively, protecting group Pg2 may be removed prior to step 1 and both phenolic
hydroxyl groups may be reacted with agent p. 2 In step 2 0-deprotection and/or N-deprotection are optionally carried out to remove groups Pg and/or Pg, to provide compound r. In embodiments wherein Pg 1 andPg 2 are carbobenzoxy (Cbz) and benzyl (Bn) respectively, both protecting groups may be removed in a single reaction via reductive debenzylation in the presence of hydrogen gas and Pd/C in dimethylactemide or lake polar aprotic solvent. In step 3 an amide coupling reaction is carried out by reaction of protected amino acid s with compound r to yield compound t. In certain embodiments the amide coupling of step 3 may utilizeO-(7 azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) in the presence of diisopropyl ethylamine (DIPEA) in polar aprotic solvent such as THF or methyl-THF. In certain embodiments of step 3, amino acid s may be lysine, diaminobutyric acid, or like amino acid wherein R 10is an aminoalkyl group (which may be suitably protected). For example, Pg1 of amino acid s may be 9-fluorenyl-methyloxycarbonyl (Fmoc), while R10 is -CH 2-CH 2-NHBoc. Step 3 may be repeated one or more times to couple additional amino acids s onto compound t. For example, in the preparation of natural arylymycin, step 3 would occur three times: first using glycine, followed by alanine, and last by N-methylserine, to provide the residues found in native arylomycin. In step 4, the protecting group Pg 1 (that was introduced in step 3 on amino acid s) is removed, and amide coupling is carried out by reacting the (deprotected) compound t with "tail group" carboxylate reagent u. In embodiments where Pg 1 is an Fmoc group, deprotection may occur using tetrabutylammonium chloride (TBAF) in polar aprotic solvent such as THF or methl-THF. The amide coupling of step 4 may be effected using ethyl-(N',N'-dimethylamino)propylcarbodiimide hydrochloride (EDC) in the presence of 1-hydroxy-7-azabenzotriazole (HOAt). Further details for tail group reagent u are provided below. In step 5, an ester hydrolysis occurs to remove the carboxy protecting group R from compound v and the resulting carboxylate compound (not shown) is reacted with amine reagent w to introduce a "warhead" group WG and provide compound x. The ester hydrolysis may utilize aqueous lithium hydroxide or other alkalai metal hydroxide in a water miscible polar solvent such as THF. The amide coupling may use O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) in the presence of DIPEA in polar aprotic solvent such as THF or methyl-THF. Further details for warhead group reagent w are provided below. Many variations on the reactions of Schemes 1A through 1E are possible and will suggest theselves to those skilled in the art. For example, the order of the reactions may be varied in many embodiments. In some instances reaction products need not be isolated but can be used in situ in the following reaction. The amine and hydroxyl protecting group chemistry, as well as the timing of protection and deprotection events, may be varied from the particular embodiments described herein. The tail group TG is in many embodiments a hydrophobic group or a group including a hydrophobic portion. For example, in natural arylomycin the group TG would be an isoundecyl (C) group, such that reagent u is isododecanoic acid. In certain embodiments the tail group reagent u may be a carboxy compound of the formula z:
R fm 1 OH
-1 x wherein: X and X 2 each independently is N or C; m and n each independently is 0, 1 or 2; Rbis: C 1- 1 2 alkylwhich may be unsubstituted or substituted one or more times with halo;
C 2-12alkenyl which may be unsubstituted or substituted one or more times with halo; C2-12alkynyl which may be unsubstituted or substituted one or more times with halo; Ci- 12alkoxy which may be unsubstituted or substituted one or more times with halo; C 2-7cycloalkyl which may be unsubstituted or substituted one or more times with C14 alkyl, halo-Ci 4 alkyl or halo; C 2-7cycloalkyloxy may be unsubstituted or substituted one or more times with C1-4alkyl, halo-C14alkyl or halo; Ci- 12alkyl-C 2-7cycloalkyl wherein the cycloalkyl moiety may be unsubstituted or substituted one or more times with C1 .4alkyl, halo-C1 .4alkyl or halo; C 2-12alkenyl-C 2-7cycloalkylwherein the cycloalkyl moiety may be unsubstituted or substituted one or more times with C1.4alkyl, halo-CI 4alkyl or halo; Ci- 12alkynyl-C 2-7cycloalkyl wherein the cycloalkyl moiety may be unsubstituted or substituted one or more times with C1 .4alkyl, halo-C1 .4alkyl or halo; Ci- 12alkyl-C 2-7cycloalkyloxy wherein the cycloalkyl moiety may be unsubstituted or substituted one or more times with C1 .4alky, halo-C1 .4alkyl or halo; C2-12alkenyl-C2-7cycloalkyloxy wherein the cycloalkyl moiety may be unsubstituted or substituted one or more times with C1 .4alkyl, halo-C1 .4alkyl or halo; Ci- 12alkynyl-C 2-7cycloalkyloxy wherein the cycloalkyl moiety may be unsubstituted or substituted one or more times with C1 .4alkyl, halo-C1 .4alkyl or halo; C2.7cycloalkyl-CI-12alkyl wherein the cycloalkyl moiety may be unsubstituted or substituted one or more times with C1 .4alkyl, halo-C1 .4alkyl or halo; C 2-7cycloalkyl-C 2-12alkenyl wherein the cycloalkyl moiety may be unsubstituted or substituted one or more times with C1 .4alkyl, halo-C1 .4alkyl or halo; C 2-7cycloalkyl-Ci-12alkynyl wherein the cycloalkyl moiety may be unsubstituted or substituted one or more times with C1.4alkyl, halo-CI1 4alkyl or halo; C 2-7cycloalkyl-Ci- 12alkyloxy wherein the cycloalkyl moiety may be unsubstituted or substituted one or more times with C1 .4alkyl, halo-C1 .4alkyl or halo; C 2-7cycloalkyl-C 2-12alkenyloxy wherein the cycloalkyl moiety may be unsubstituted or substituted one or more times with C1.4alkyl, halo-CI 4alkyl or halo; C 2-7cycloalkyl-C 1-12alkynyloxy wherein the cycloalkyl moiety may be unsubstituted or substituted one or more times with C1 .4alkyl, halo-C1 .4alkyl or halo; phenyl-C 1-12alkyl wherein the phenyl moiety may be unsubstituted or substituted one or more times with C 1 .4alkyl, halo-C14 alkyl or halo; phenyl-C 2-1 2alkenyl wherein the phenyl moiety may be unsubstituted or substituted one or more times with C1. 4 alkyl, halo-Ci 4 alkyl or halo; phenyl-C1-12alkynyl wherein the phenyl moiety may be unsubstituted or substituted one or more times with C1. 4 alkyl, halo-Ci 4 alkyl or halo; phenyl-CI-1 2alkyloxy wherein the phenyl moiety may be unsubstituted or substituted one or more times with C1. 4alkyl, halo-C1.4alkyl or halo; phenyl-C2-12alkenyloxy wherein the phenyl moiety may be unsubstituted or substituted one or more times with CI1 4alkyl, halo-C1.4alkyl or halo; or phenyl-C1-12alkynyloxy wherein the phenyll moiety may be unsubstituted or substituted one or more times with C1. 4alkyl, halo-C1.4alkyl or halo; and R° and Rd each independently is: C1 .4alkyl, halo-Ci 4 alkyl or halo. In certain embodiments the warhead group reagent w may be glycine nitrile (H 2N-CH 2-CN) so that the group WG is -CH 2CN. In other embodiments WG may be heteroaryl, amido, epoxy, or other group. Accordingly, the invention provides a method for making an arylomycin ring of formula o Pg 2 4 o O 5 OH0
R2 R3 (R) R HN H N N! 00 1 8 Pg 0 R wherein: Y is halogen (fluoro, chloro, bromo or iodo); R is: hydrogen; or C14alkyl; and may be the same or different on each occurrence; R 1, R 2, R 3, R4,R 5 and R e ach independently is: hydrogen; C1 .4alkyl; halo-C1 .4alkyl; halo; amino; amino-Cialkyl; hydroxy; hydroxy-C1.6alkyl; cyano; cyano-C1.alkyl; or nitro, wherein the amino and hydroxyl moieties may optionally include a protecting group; R7 is: hydrogen; or C1. 4alkyl; R' is: hydrogen; C 14 alkyl; halo-C1 4 alkyl; halo; amino; amino-C1. 4alkyl; hydroxy; hydroxy-C1. 6alkyl; cyano; or cyano-C -16alkyl, wherein the amino and hydroxyl moieties may optionally include a protecting group; Ra is: hydrogen; or C 1 .4alkyl; and may be the same or different on each occurrence, or two R groups may form a C 2-6 alkylene that, together with the atoms to which they are attached, may form a five or six-membered ring; Pg' is an optional amine protecting group; and Pg2 is an optional hydroxyl protecting group; the method comprising: reacting a phenyl boronate compound of formula m:
2 4 Pg 0 R5
ROB ORa R6 OR HN H2N O O
R8 M or a salt or solvate thereof, with a phenyl halide compound of formula e; OH R1 xY
R2 R3
N OH Pg1 0 e
or a salt or solvate thereof, to form a compound of formula n;
RaO, BORa OH B R1 y R6 OPg 2
R2 R3 R7 R R4 HR P9 N ROR 8 Me 0 R H O
or a salt or solvate thereof; and
treating the compound of formula n with chloro(crotyl)(tri-tert-butylphosphine)palladium(II), to make the compound of formula o; or a salt or solvate thereof.
In another embodiment, the invention provides a method of making an arylomycin ring of formula
0
2 4 Pg U ~ 5 OH R1 OH R7
R2 R3 (R) R HN (S) NH 9 O N N! 00 Pg1 0 R8 0
wherein R, R', R 2, R3 , R4 ,R , R , R 7, R, Pg' and Pg 2 are as defined herein;
the method comprising: reacting a phenyl boronate compound of formula m: g2 4
0 R5
ROB ORa R6 OR HN H2N O O
R8 M or a salt or solvate thereof, with a phenyl halide compound of formula e; OH R1 Y
R2 R3
N OH Pg1 0 e or a salt or solvate thereof, in the presence of chloro(crotyl)(tri-tert-butylphosphine)palladium(II), to form a compound of formula y;
Pg 2 4 1 RO OH O
R1 (R) 8
/3 R R7 NH 2 R 2t
0sOH v N IPgi O
or a salt or solvate thereof; and cyclizing compound vby forming an amide bond to make the the compound o; or a salt or solvate thereof. In certain embodiments, the subject methods may further comprise:
reacting a compound of formula k
P92 4
11 7 Y R6 (R) OR NH O0 k pgeNH R8 or a salt or solvate thereof, with a boronating agent to form a compound of formula 1
P 92
OR a N B ORB (R) OR NH 0 pg1-NH R8
or a salt or solvate thereof; and removing the protecting group Pgi to form the compound of formula m 4 F9g2 0 R5
RaO' B
ORa R6 OR HN H2 N O O
R8 M or a salt or solvate thereof, wherein R, R 1, R 2, R3 , R4,R , R , R 7, R, Pg 1 and Pg 2 are as defined herein. In certain embodiments, the subject methods may further comprise: reacting a compound of formula h 4
HO R5 1 7 Y") R 6 (R) OR H 2N O h with an amino acid of formula i
H OH Pgi'N O R8 to form a compound of formula j 4
HO 5
Y ~R 7 6 R (R) OR H HN pg1-N O 0 R8
or a salt or solvate thereof; and introducing a hydroxyl protecting group Pg2 , to form the compound of formula k
P92 4
11 7 Y R6 (R) OR NH O0 k pgeNH R8 or a salt or solvate thereof, wherein Y, R, R', R2 , R3 , R4 ,R, R 6, R 7, R, Pg and Pg 2 are as defined herein.
In certain embodiments the subject methods may further comprise: esterifying a compound of formula g 4
HO 5 7
R6 (R) OH H2 N 0 or a salt or solvate thereof,
to form the compound of formula h 4
HO R5 1 7
R6 (R) OR H 2N 0 or a salt or solvate thereof, wherein Y, R, R, R2 , R3 , R4 ,R 5 , R 6, R 7, Pg and Pg 2 are as defined herein. In certain embodiments the subject methods may further comprise:
halogenation of a compound formula f 4
HO 5 7
6 R (R) OH H2Ni O 0 or a salt or solvate thereof, to form the compound of formula g
HO5 7 Y R6 (R) OH H2N 0 or a salt or solvate thereof, wherein Y, R, R', R2, R3 , R4,R, R, R 7, Pg and Pg 2 are as defined herein. In certain embodiments the subject methods may further comprise: reducing a compound of formula d OH R1 Y
g-N\O 0
to form the compound of formula e OH R1 Y
R2 R3
N OH Pg1 O e or a salt or solvate thereof, wherein Y, R, R', R2, R 3, and Pg' are as defined herein. In certain embodiments the subject methods may further comprise: reacting a compound of formula c OH R1 Y3
R2 R3 Pgi,' OH H 0 C or a salt or solvate thereof, with trioxane, to form the compound of formula d OH R1 Y
R2 R3 Pgi' O -NO 0
or a salt or solvate thereof, wherein Y, R, R', R2, R 3, and Pg' are as defined herein. In certain embodiments the subject methods may further comprise: halogenating a compound of formula a OH R1
R2 R3 OH H 2N i O a or a salt or solvate thereof, to form a compound of formula b OH R1 y
R2 R3 OH H 2N O b or a salt or solvate thereof; and introducing an amine protecting group to the compound of formula b to form the compound of formula c OH R1 Y
Pgi,' OH H O C or a salt or solvate thereof; wherein R, R', R 2, R 3, and Pg' are as defined herein. In certain embodiments the subject methods may further comprise: reacting the compound of formula o 2 Pg 4 1 OH0
- RR7 R2 R3 (R) R HN (S)O H N Nj 00 Pg1 0 R8 or a salt or solvate thereof; with an alkylating reagent of formula p R 9-X 2 or a salt or solvate thereof, to form a compound of formula g 2 4 Pg R9 06
6 R1 RR
R 2 (R) R HN ( N )O H 00 N! Pg1 0 R8 or a salt or solvate thereof; wherein R, R', R 2, R3 , R4,R', R , R 7, R, R 9, X, Pg and Pg2 are as defined herein. In certain embodiments the subject methods may further comprise: removing the amine protecting group Pgi, and optionally removing the hydroxyl protecting group Pg2 from the compound of formula g Pg 2 4
R9 0
R)R3(R) R HN (3) H! 0 N 0 Pg1 0 R8 or a salt or solvate thereof; to form a compound of formula r 4
R9 HO 5
O R~~ R6HN r0H
or asalt or solvate thereof; whereinR,RR 2 ,R 3 ,R 4 ,RRR7 ,RandR 9 are as definedherein.
In certain embodiments the subject methods may further comprise: reacting the compound of formula r
R9- HO 5
R1 90HO5 R7
R2! / R3 (R) R HN (S)H N (s) H 0 R8 or a salt or solvate thereof;
with an amino acid reagent of formula s
Pg 1 0
HN OH R10s
or a salt or solvate thereof;
to form a compound of formula t 4
R9 HO R5
R1 ~ R R2 R 3 R 6(R) R o HN (S)~H Pg N (s) R10 0 R8 or a salt or solvate thereof; wherein R, R', R 2, R3 , R4 ,R , R , R 7 , R, R 9 , R1 °and Pg are as defined herein.
In certain embodiments the subject methods may further comprise: removing the amine protecting group Pg from, and reacting the compound of formula t 4
R 9 OHO R5
R R2 R 3 R 6(R) R o HN (S)~H Pg N (s) R10 0 R8 or a salt or solvate thereof;
with a reagent of formula u TG-COOH u or a salt or solvate thereof;
to form a compound of formula v
R5 R9 HO
R R R2 / R3 R 6(R) R O HN T M'Y (s N! 9 N N 0- 0 v 10 0 R 8 0 R or a salt or solvate thereof; wherein R, R', R 2 , R3 , R4 ,R', R 6, R 7, R', R 9 , R 14, Pg and TG are as defined herein. In certain embodiments the subject methods may further comprise:
hydrolyzing, and reacting the compound of formula v 4
R9 HO 5
2 R 3 R6(R) R o HN (S)~H TGy N N 0 v 8 o Rio 0 R or a salt or solvate thereof; and
reacting the hydrolysis product of compound v with a reagent of formula u H 2N-WG w or a salt or solvate thereof;
to form a compound of formula x 4
R9 HO 5
R2 / R6R O HN WG
N )0 R3 (R) M O Ri0 O R 8
or a salt or solvate thereof; wherein R, R', R 2, R3 , R4,R , R 6, R 7, R', R 9, R 14, Pg', TG and WG are as defined herein. In certain embodiments of the subject methods, the reagent u is a compound of formula z
Rb R ((C xid)n O M X1 /\ b OHz -Y x2 wherein:
X' and X 2 each independently is N or C; m and n each independently is 0, 1 or 2; Rbis: Ci-12alkyl which may be unsubstituted or substituted one or more times with halo;
C 2-1 2alkenyl which may be unsubstituted or substituted one or more times with halo; C 2-1 2alkynyl which may be unsubstituted or substituted one or more times with halo; Ci-1 2alkoxy which may be unsubstituted or substituted one or more times with halo; C2-7cycloalkyl which may be unsubstituted or substituted one or more times with C14alkyl, halo-C1 4 alkyl or halo; C 2-7cycloalkyloxy may be unsubstituted or substituted one or more times with C1-4alkyl, halo-C1 4 alkyl or halo; Ci-1 2alkyl-C 2-7cycloalkyl wherein the cycloalkyl moiety may be unsubstituted or substituted one or more times with C1.4alkyl, halo-CI 4alkyl or halo; C 2-1 2alkenyl-C 2-7cycloalkyl wherein the cycloalkyl moiety may be unsubstituted or substituted one or more times with CI1 4alkyl, halo-CI 4alkyl or halo; CI-1 2alkynyl-C 2-7cycloalkyl wherein the cycloalkyl moiety may be unsubstituted or substituted one or more times with C1.4alkyl, halo-CI 4alkyl or halo; Ci-1 2alkyl-C 2-7cycloalkyloxy wherein the cycloalkyl moiety may be unsubstituted or substituted one or more times with CI1 4alky, halo-CI 4alkyl or halo; C 2-1 2alkenyl-C 2-7cycloalkyloxy wherein the cycloalkyl moiety may be unsubstituted or substituted one or more times with C 4 alkyl, halo-CI1 4alkyl or halo; Ci-12alkynyl-C2-7cycloalkyloxy wherein the cycloalkyl moiety may be unsubstituted or substituted one or more times with CI1 4alkyl, halo-CI 4alkyl or halo; C 2-7cycloalkyl-Ci-1 2alkyl wherein the cycloalkyl moiety may be unsubstituted or substituted one or more times with C 4 alkyl, halo-CI 4alkyl or halo; C2.7cycloalkyl-C2-12alkenyl wherein the cycloalkyl moiety may be unsubstituted or substituted one or more times with C 4 alkyl, halo-CI 4alkyl or halo; C 2-7cycloalkyl-Ci-12alkynyl wherein the cycloalkyl moiety may be unsubstituted or substituted one or more times with C 4 alkyl, halo-CI 4alkyl or halo; C 2-7cycloalkyl-Ci-1 2alkyloxy wherein the cycloalkyl moiety may be unsubstituted or substituted one or more times with C1.4alkyl, halo-CI 4alkyl or halo; C 2-7cycloalkyl-C 2-1 2alkenyloxy wherein the cycloalkyl moiety may be unsubstituted or substituted one or more times with C 4 alkyl, halo-CI 4alkyl or halo; C 2-7cycloalkyl-Ci-1 2alkynyloxy wherein the cycloalkyl moiety may be unsubstituted or substituted one or more times with C1.4alkyl, halo-CI 4alkyl or halo; phenyl-C 1-12alkyl wherein the phenyl moiety may be unsubstituted or substituted one or more times with C 1 .4alkyl, halo-C 14 alkyl or halo; phenyl-C 2-12alkenyl wherein the phenyl moiety may be unsubstituted or substituted one or more times with C 1 .4alkyl, halo-C 14 alkyl or halo; phenyl-CI-1 2alkynyl wherein the phenyl moiety may be unsubstituted or substituted one or more times with C1. 4 alkyl, halo-C14 alkyl or halo; phenyl-C1-12alkyloxy wherein the phenyl moiety may be unsubstituted or substituted one or more times with C1. 4alkyl, halo-C1. 4alkyl or halo; phenyl-C 2-1 2alkenyloxy wherein the phenyl moiety may be unsubstituted or substituted one or more times with C1. 4alkyl, halo-CI 4alkyl or halo; or phenyl-C1-12alkynyloxy wherein the phenyll moiety may be unsubstituted or substituted one or more times with C1. 4alkyl, halo-CI 4alkyl or halo; and R and R° each independently is: C1. 4alkyl, halo-C1. 4alkyl or halo.
In such embodiments the resulting TG group on compounds vand x is such that TG is
R q()m 'iV1 q
Rb
In certain embodiments of the subject methods, the reagent w is cyano-C1 4 alkylamino, such as glycine nitrile or H 2N-CH 2-CN. so that the group WG is cyano-CI 4alkyl such as -CH 2CN. In other embodiments WG may be heteroaryl, amido, epoxy, or other group. In such embodiments, the compound of formula x may be of formula A 4
R9 HO 5
X (R R N X1 n,(R H R 1 0 HN 2K (S)NH 0 N O A 0 R 10 0 R8 wherein RR 2, R 3, R 4,R , R 7, RR 9, R 10, Ra, , R°, m and n are as defined herein. Experimental Section All chemicals, reagents, and solvents were purchased from commercial sources when available and used without further purification. All reactions were carried out under N 2 atmosphere and monitored by HPLC. NMR spectra were recorded with a Bruker Avance III spectrometer using a 5 mm BBFO probe at 400 MHz for 1 H acquisitions. Chemical shifts were referenced to the residual 1 H solvent signals (DMSO-d6, 2.50). Signals are listed as follows: chemical shift in ppm (multiplicity identified as s = singlet, d = doublet, t = triplet, q = quartet, m= multiplet, br = broad; coupling constants in Hz; integration). Mass spectrometry (MS) was performed via electron scatter ionization (ESI) sources. List of Abbreviations AcOH Acetic acid AIBN 2,2'-Azobis(2-methylpropionitrile) Atm. Atmosphere (BOC)20 di-tert-Butyl dicarbonate
CbzCl carboxybenzyl chloride CDMT 6-chloro-2,4-dimethoxy-s-triazine DCM Dichloromethane/Methylene chloride DIAD Diisopropyl azodicarboxylate DIPEA Diisopropylethylamine DMA Dimethylacetamide DMAP 4-Dimethylaminopyridine DME 1,2-Dimethoxyethan DMF NN-Dimethylformamide DMSO Dimethyl sulfoxide DPPF 1,1'-Bis(diphenylphosphino)ferrocene EDCI Ethyl-(N',N'-dimethylamino)propylcarbodiimide hydrochloride Et 20 Diethyl ether EtOH Ethanol/Ethyl alcohol EtOAc Ethyl acetate HATU 2-(1H-7-Azabenzotriazol-1-yl)--1,1,3,3-tetramethyl uronium hexafluorophosphate IBCF Isobutyl chloroformate HBTU O-Benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate HOAt 1-Hydroxy-7-azabenzotriazole HOBt 1-Hydroxybenzotriazol HPLC High pressure liquid chromatograph KOAc Potassium acetate METHF Methyltetrahydrofuran RP HPLCReverse phase high pressure liquid chromatograph i-PrOH Isopropanol/isopropyl alcoho LCMS Liquid Chromatograph/Mass Spectroscopy MeOH Methanol/Methyl alcohol MSA Methanesulfonic acid MW Microwave NBS N-Bromosuccinimide NMM N-methylmorpholine NMP 1-Methyl-2-pyrrolidinone PSI Pound per square inch PyBOP (Benzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate r.t. Room temperature TBAF Tetrabutylammonium chloride TFA Trifluoroacetic aci THF Tetrahydrofuran
TLC Thin layer chromatography TSOH Toluenesulfonic acid Example 1 Preparation of (S)-2-(((benzyloxycarbonyl)(methyl)amino)-2-(4-hydroxy-3-iodophenylacetic acid A5 (1) CbzCI, 1.25 eq OH OH Na 2CO 3 , 2.1 eq OH Dioxane,2 w NH 3H 20,7.4 w H 20, 8w 1 2, 0.8 eq 10-15 °C, 2 h
OH (2) LiOH, 2.5 eq Cbz,.. N OH OH -10 ~ 0 C H 2N 2h O 10-20 °C, 1 h H 0 Al A2 A3
OH TFA, 11 eq OH (CH 20)3, 4 eq I DCM, 6.5 w TsOH, 4.3 eq Et 3SiH, 4 eq
2-MeTHF, 8.5 w Cbz-N 0 20-30 °C, 16 h N OH MgSO 4 , 2 w l 70~75 °C, 1 h O Cbz 0 A4 A5 Scheme 2A The synthesis of (S)-2-(((benzyloxy)carbonyl)(methyl)amino)-2-(4-hydroxy-3-iodophenyl)acetic acid A5 is illustrated in Scheme 2A. (S)-2-amino-2-(4-hydroxy-3-iodophenyl) acetic acid (A2): To a glasslined-reactor (3000 L), were added NH 3-H 20 (1246 kg, 7.4 w) and cpd. Al (167 kg, 999 mol, 1 equiv.). The rxn mixture was cooled to -5 C. 12 was added in 20 portions (202.8 kg, 799 mol, 0.8 equiv.) over a period of 6 h at -10~-5 C (slightly exotherm was found. max temp. -1 C). The mixture was stirred at -5-0 C for 2 h. The mixture was concentrated under vacuum at 50-55 C jacket temeprature (I.T.: 0-42 °C) over 14 h until the pH dropped to 9.7 (9.5-9.8). The residue was diluted with water (2040 kg, 12 w). The solution was acidified by adding 15% HCl aq. (600 kg, 3.6 w) dropwise at 20-32 C to the pH = -6.3 (5.5-6.4). The mixture was stirred at 25-32 C for 1 h. The slurry was centrifuged and rinsed with water twice (340 kg, 2 w & 170 kg, 1 w), and acetone twice (100 kg, 0.6 w & 80 kg, 0.5 w). The wet cake was dried under vacuum on 45-50 C (jacket temperature) for 24 h to afford 141 kg of A2 with 97.9 A% & 87.7 w% (by qNMR) purity & 0.4 w% water content in 48.2% yield (uncorrected) as a light brown solid. 1 H NMR (400 MHz; DMSO; Me4Si), 6(ppm): 68.25 (s, 2H), 7.71 (d, J= 2.0 Hz, 1H), 7.18 (dd, J = 8.4, 2.0 Hz, 1H), 6.86 (d, J= 8.3 Hz, 1H), 4.20 (s, 1H). (S)-2-(((benzyloxy)carbonyl)amino)-2-(4-hydroxy-3-iodophenyl)acetic acid (A3): To a glasslined- reactor (3000 L), were added water (1140 kg, 8 w) and Na 2 CO 3 (108.2 kg, 1021 mol, 2.1 equiv.) with stirring. A2 (140.1 kg, 478 mol, 1.0 equiv.) was quickly added and the mixture was stirred for 20min (all A2 dissolved). The rxn mixture was cooled to 10-15 C. A solution of CbzC1 (102 kg, 598 mol, 1.25 equiv.) in 1,4-dioxane (280 kg, 2 w) was added dropwise over 4 hrs. while keeping the internal temperature between 10 to 15 C. The reaction mixture was stirred at 10-20 C for additional 2 hrs. Upon the reaction completion, the rxn mixture was concentrated at 45-55 C (water batch 55-60 C) to remove most of 1,4-dioxane (-100 kg 1,4-dioxane & water were collected). The residue was cooled to 20-30 C and aq. solution of LiOH-H 20 (51 kg, 1215 mol, 2.5 equiv. in 2140 kg of water, 15 w) was added over 1 h. The mixture was stirred for 1 h at 20-30 C. IPC on HPLC: 81.8 A% of A3 (RT = 6.1 min), 0.3 A% of bis-Cbz product (RT = 7.6 min) & 1.3 A% of A2 remained. The aqueous solution was extracted with the 1st portion of DCM (780 kg, 5.5 w) and the phases were separated. The 2 portion of DCM (780 kg, 5.5 w) was added to the aqueous phase. About 15% aq. HC (300 kg) was added dropwise at 20-30 C adjust the pH to 2-3 (slightexothermic & large amount of gas releasedas pH dropped to-6). The phases were separated and the aqueous was extracted with 3 rd portion of DCM (500 kg, 3.5 w). The organic phases (the 2" and 3 rd portion of DCM extracts) were combined and dried over Na 2SO4 (50 kg) for 1 hr. The mixture was filtered. The solid was washed with a small amount of DCM and the filtrate was concentrated at 40-50 C (jacket temperature, 55-60 C) to remove most of the solvent. EtOAc (210 kg, 1.5 w) was added and the mixture was continuously concentrated under vacuum at 40-50 C to purge the residual DCM. EtOAc (210 kg, 1.5 w) was again added and then concentrated under vacuum at 4050 C to -300 kg. petroleum ether (600 kg, 4.3 w) was added over 30 min (large amount of white solids precipitated out). The slurry was cooled to 10-15 C and stirred for 2 h at 10-15 C. The mixture was filtered & the cake was washed with petroleum ether/EtOAc (120 kg, 3/1, w/w, 0.9 w). The wet cake was dried under vacuum at 40-50 C (water bath, 45-50 C)for 30 h to afford 205.1 kg of A3 with 94 A%
& 79.3 w% (by qNMR) purity in 98.4% yield (uncorrected) as a light-brown solid. 1 H NMR (400 MHz; DMSO; Me4Si), 6(ppm): 6 12.80 (s, 1H), 10.39 (s, 1H), 8.04 (d, J= 8.0 Hz, 1H), 7.70 (d, J= 2.1 Hz, 1H), 7.39 - 7.26 (m, 5H), 7.22 (dd, J= 8.4, 2.1 Hz, 1H), 6.83 (d, J= 8.3 Hz, 1H), 5.09 - 4.99 (m, 3H). (S)-benzyl 4-(4-hydroxy-3-iodophenyl)-5-oxooxazolidine-3-carboxylate (A4): To a 3000 L reactor, were charged 2-MeTHF (840 kg, 5 w) and A3 (169.4 kg, 388.6 mol, 1 equiv.). The mixture was stirred for 10 min (all solid was dissolved). TsOH-H 20 (317.8 kg, 1671 mol, 4.3 equiv.) was then added and followed by MgSO 4 (332 kg, 2 w). The reactor was degassed and refilled with N 2 3 times. The suspension was heated to 70-75 C. A solution of (CH2O)3 (140 kg, 1554 mol, 4 equiv.) in 2 MeTHF (580 kg, 3.5 w) was added dropwise over 3 hrs. at 70-75 C. The rxn mixture was stirred at 7075 °C for another 1 hr. (a sample was taken for HPLC analysis: A3 < 5 A%). The rxn mixture was cooled to 25-30 C and 2700 kg (16 w) of water (15-20 C) was added over 3 hrs. (mildexothermic. IT rose to 28 C from 20 C). Stopped agitation and allowed separation of phases. The aqueous phase was extracted with EtOAc (800 kg, 5 w). The organic phases were combined and washed with aq. Na 2CO 3 which was made by dissolving 29 kg Na 2CO 3 in1600 kg of water (the pH of the resulting aqueous was -9). The phases were separated and the organic phase was washed with brine (50 kg NaCl in 600 kg water). The organic phase was dried over anhydrous Na 2SO 4 (50 kg) for 1 hr. before filtration. The filtrate (combined with the filtrate from the batch with 30.6 kg of A3) was concentrated at 4045 C (jacket temperature 45-50 C) under vacuum to 300-350 kg stage. Petroleum ether (400 kg, 2 w) was added and themixture was concentrated under vacuum at 40-45 C again to 350-400 kg stage again (a large amount of solid was precipitated out). Petroleum ether (780 kg, 4 w) was added. The suspension was cooled to 15-25 C and stirred for 1 hr. The suspension was filtered. The solid was dried under vacuum at 35-45 C for 24 h to afford 142 kg of A4 with 89.1 A% (HPLC) & 86.4 w% (by qNMR) purity in 69.6% yield as a light brown solid. 1 H NMR (400 MHz, DMSO) 6 10.50 (s, 1H), 7.70 (s, 1H), 7.43 - 7.19 (m, 5H), 7.03 (s, 1H), 6.87 (d, J= 8.3 Hz, 1H), 5.58 (d, J= 43.9 Hz, 2H), 5.27 (s, 1H), 5.14 (d, J= 12.5 Hz, 1H), 5.05 (s, 1H). (S)-2-(((benzyloxy)carbonyl)(methyl)amino)-2-(4-hydroxy-3-iodophenyl)acetic acid (A5): To a 3000 L reactor, were charged DCM (920 kg, 6.5 w), A4 (142 kg, 324 mol, 1 equiv.), TFA (407 kg, 3559 mol, 11 equiv.) and Et 3SiH (150.5 kg, 1294 mol, 4 equiv.). The mixture was stirred at 25-30 C for 13 hrs. (IPC on HPLC showed: 88.3 A% of A4 and 2.6 A% of A4 remained). The mixture was concentrated under vacuum at 25-45 C (jacket temperature: 40-45 C) to -400 kg. The residue was cooled to 20-30 C and DCM (1400 kg, 10 w) was added. Na 2 CO 3 solution (140 kg of Na 2 CO 3 dissolved in 1260 kg water) was added to adjust the pH of the DCM solution to-9. The phases were separated. DCM (700 kg, 5 w) was added to aqueous and then the pH of the mixture was adjusted to -2 with -100 kg 30% HCl. The mixture was then stirred at 15-25 C for -2 hrs. before filtration. The cake was rinsed with water (140 kg, 1 w) and slurried in DCM (650 kg, 4.5 w) at 15-25 C for -1 hr. The slurry was centrifuged and rinsed with DCM (140 kg, 1 w). The wet cake was dried at 35-45 C (jacket temperature: 40-45 C) for 30 h under vacuum. About 101 kg of A5 was obtained in 70.8% yield (uncorrected) as an off-white solid (98.9 A% purity, >99% de, 91.5 w% (by qNMR) & 1.3 w% KF). 1 H NMR (400 MHz; DMSO; Me4Si), 6 (ppm): 1H NMR (400 MHz, dmso) 6 13.10 (s, 1H), 10.55 (s, 1H), 7.56 (s, 1H), 7.41 - 7.28 (m, 5H), 7.12 (d, J= 8.3 Hz, 1H), 6.90 (d, J= 8.3 Hz, 1H), 5.65 (s, 1H), 5.13 (s, 2H), 2.66 (s, 3H). Example 2 Preparation of (5-((S)-2-((S)-2-aminopropanamido)-3-methoxy-3-oxopropyl-2 (benzyloxy)phenyl)boronic acid hydrochloride (A14)
HO HO HO NH4 0H, 13.5 w 12, 1.08 eq | 2 eq. SOC1 2 I (S) OH (s (S) s) OH(S) OMe (s) H 2N -5-0 °C, 2 h H2 N 4 w MeOH H2 N O O 60-65°C,4h 0 A6 A7 A8
H OH HO 0.97 eq. BnBr BnO BocN s O 1.7 eq. K 2CO3 4 w acetone I A9 Me ,(s OMe , (S) OMe 0 1.15 eq. CDMT, H HN 5 C2h NH 2.55 eq. NMM, BocN s::O BNH 0 11wDCM M -5-0 °C, 2 h Me A10 Me All
,B-B' BnO
0 0 0 1B 1.5 eq 0 (s) OMe 10 M HCI-MeOH, 1.6 v NH Pd(dppDCl 2 , 0.075 eq NH O o 20~25 °C, 3 h KOAc, 4 eq (dry) Boc O 6 vACN Slurry DMSO7v Me 90 °C, 3 h A12
BnO BnO
O B NalO4, 1.25 eq HO B 0 OMe_, HO HN(S) HNN OMe H2N O 4w%HCI, 0.1 eq CIHH 2N O0 . HO 2-MeTHF, 1.7 w z~Me Me HCI 15-20 °C, 5 h A13 A14 Scheme 2B
The synthesis of(5-((S)-2-((S)-2-aminopropanamido)-3-methoxy-3-oxopropyl)-2 (benzyloxy)phenyl)boronic acid hydrochloride A14 is illustrated in Scheme 2B.
(S)-2-amino-3-(4-hydroxy-3-iodophenyl)propanoic acid (A7): To a 3000 L flask, were added A6 (147.3 kg, 813 mol,1 equiv.) and conc. NH H 3 20 (25%, 1980 kg, 13.5 w). The white suspension was cooled to -10-0 °C. 12 (223 kg, 878 mol, 1.08 equiv.) was added in 40 portions over a period of -5 hrs. at -10-0 °C. The solution was stirred at -10-0 °C for -2 hrs. (a sample was taken from the mixture and diluted with water for IPC on HPLC: 86.4 A% of A7 & 11.3 A% of bis
iodide (not shown in Scheme 2B) and 2.3 A% of A6 remained). It was then concentrated under vacuum at
0-40 C for -28 hrs. until the pH of the residue dropped to 9.6. The residue solution was cooled to 20-30 C. Aqueous HCl (18 w%) was added dropwise at 20-30 C over 10 h to adjust the pH to 8 before A7 (0.25 kg) was added as seeds. After the mixture was continuously stirred for -1 h at 20-30 C, the pH of the mixture was continuously adjusted using aqueous HC (18 w%) to 7.4 over -3 hrs. and 6.6 over - 1 hr., and stirred for 1 hr. at each pH stage . The resultant was stirred at 20-30 °C for 2 h (a total of-1200 kg of 18 w% aq. HCl was used for crystallization). The slurry was centrifuged. The wet cake was washed twice with water (230 kg, 1.6 w, each) and then twice with acetone (230 kg, 1.6 w, each). The solid was dried under vacuum at 50-60 Cfor -48 hrs. to afford 156.6 kg of A7 with 96 A% purity & 2.5 w% water content as a light brown solid in 62.6% yield (uncorrected; subtract 0.25 kg of A7 seed). (S)-methyl 2-amino-3-(4-hydroxy-3-iodophenyl)propanoate (A8): To a 2000 L reactor, were added MeOH (640 kg, 4 w) and A7 (156 kg, 508 mol, 1 equiv.) with stirring. The reactor was degassed and re-filled with N 2 twice. The resulting suspension was cooled to -5 °C to 5 °C. SOC12 (122 kg, 1029 mol, 2 equiv.) was added dropwise over 2.5 hrs. while maintaining I.T. < 5 °C (exothermic. max 4.5 °C. All solid dissolved). The rxn solution was stirred at -5 °C to 5 °C for1 hr. and then heated to 55-65 °C slowly (- 3 h) and stirred for 2 h (a sample was taken for IPC on HPLC: 96.9 A% of A8 & 0.4 A% of A7 remained). The mixture was cooled to <50 °C and concentrated under vacuum at 40-55 °C to -450 kg of residue (solids started to be precipitate out). EtOAc (240 kg, 1.5 w) was added to the residue and the mixture was concentrated under vacuum at 40-55 °C to -400 kg of residue. A second part of EtOAc (240 kg, 1.5 w) was added to the residue and themixture was concentrated again under vacuum at 30-55 °C to -400 kg of residue. A third part of EtOAc (125 kg, 0.8 w) was added to the residue and the mixture was concentrated under vacuum at 30-45 °C to -400 kg of the final residue. EtOAc (125 kg, 0.8 w) was thus added to the residue and followed by adding petroleum ether (95 kg, 0.6 w). The suspension was cooled to 15-25 °C and stirred for -1 hr. The mixture was filtered and the cake was rinsed with EtOAc/petroleum ether (65 kg/ 55 kg, 0.45 w/ 0.35 w). The wet cake was dried under vacuum at 40-50 °C for 36 hrs. and -161 kg of A8 HCl salt with 96.3 A% & 86.5 w% (by qNMR) purity in 88.6% yield (uncorrected) was obtained as a white solid. 1 H NMR (400 MHz; DMSO; Me4Si), 6 (ppm): 1H NMR (400 MHz, dmso) 6 10.49 (s, 1H), 8.67 (s, 2H), 7.53 (d, J= 1.6 Hz, 1H), 7.32 (d, J= 50.0 Hz, 1H), 7.03 (dd, J= 8.3, 1.6 Hz, 1H), 6.91 (d, J= 8.2 Hz, 1H), 4.17 (t, J= 6.2 Hz, 1H), 3.68 (s, 2H), 3.02 (qd, J= 14.2, 6.4 Hz, 1H). (S)-methyl 2-((S)-2-((tert-butoxycarbonyl)amino)propanamido)-3-(4-hydroxy-3 iodophenyl)propanoate (A1O): To a 1000 L reactor, were added DCM (780 kg, 11 w), A9 (43 kg, 227 mol, 1.15 equiv.) & CDMT (39.9 kg, 227 mol, 1.15 equiv.). The reactor was degassed and refilled with N 2 twice. NMM (33.9 kg, 193.3 mol, 1.7 equiv.) was then added dropwise over -40 min, while maintaining the I.T. at -5 to 5 °C (slightly exothermic). The suspension was stirred at -5 to 5 °C for 1 hr. before use. To another 2000 L reactor, were added DCM (390 kg, 5.5 w), A8-HCI (70.6 kg, 197.4 mol, 1 equiv.) & NMM (17 kg, 167.8 mol, 0.85 equiv.). The reactor was degassed and refilled with N 2 twice. The suspension was cooled to -5 to 0 °C and the solution of A9/CDMT/NMM/DCM was added dropwise over 2 hrs. below 0 °C (slightly exothermic). The mixture was stirred at -5-0 C for 2 hrs.(a sample was taken from the rxn mixture for IPC on HPLC: 75 A% of A1 & 1.9 A% of A8-HCI remaining). The rxn was quenched by adding a solution of citric acid (9 kg dissolved in 360 kg of water) dropwise over 30 min below 0 C and stirred for additional -30 min. before filtration. The phases (the filtrate) were separated and the organic phase was washed with aqueous NaHCO3 (6 kg dissolved in 60 kg water), and then water (180 kg x 2). The organic phase was concentrated under vacuum at 30-40 C to -100 kg of residue. Acetone (45 kg, 0.6 w) was added and the mixture was concentrated under vacuum at 35-45 C to -100 kg of residue again. This repeated one more time to purge DCM. More acetone (240 kg, 3.4 w) was added and the solution was cooled to 15-25 °C. The AO/acetone solution (330 kg) was used directly for next step. MS (ESI, m/z): 493 (M *). (S)-methyl 3-(4-(benzyloxy)-3-iodophenyl)-2-((S)-2-((tert butoxycarbonyl)amino)propanamido)propanoate (All): To a 2000 L reactor, were added the solution of S,S-E21 in acetone (725 kg solution, calculated as 230.9 kg of A1 from 150.6 kg of A8 HC in 100% yield), K 2 CO3 (100 kg, 723.5 mol, 1.7 equiv.) and Benyl Bromide (70 kg, 409.3 mol, 0.97 equiv.). The mixture was heated to 50-58 C and stirred for 2 hrs. (a sample was taken for IPC on HPLC: 65 A% of All & nil of A1 remaining). Themixture was cooled to 25-30 C and filtered. The cake was rinsed with DCM (250 kg, 1.7 w of A8-HC). The combined filtrate was concentrated under vacuum at 30-50 °C to -300 kg of residue and petroleum ether (800 kg, 5.3 w of A8-HC1) was added over 20 min. The mixture was cooled to 0~10 C and stirred for 1 h. The slurry was filtered and the cake was rinsed with DCM/petroleum ether (45 kg/90 kg). The wet cake (-240 kg) was dissolved in DCM (500 kg, 3.3 w of A8-HC) at 20-30 °C. Petroleum ether (500 kg, 3.3 w of A8 HC) was added dropwise over 40 min. The slurry was cooled to 0-5 °C and stirred for 1 h. The slurry was filtered. The wet cake was slurried in DCM/petroleum ether (250 kg/500 kg) at 20-30 °C for 0.5 h. The slurry was filtered and the cake was rinsed with DCM/petroleum ether (45 kg/90 kg). The wet cake was dried under vacuum at 20-40 C (jacket temperature, 4045 °C) for -30 hrs. About 134.6 kg of Al1 was obtained as an off-white solid with 96.6 A% purity, >99% de & 96.1 w% (by qNMR) in 54.9% yield (uncorrected) over 2 steps from 150.6 kg of A8-HC. 1 H NMR (400 MHz; DMSO; Me4Si), 6 (ppm): 1H NMR (400 MHz, dmso) 6 8.09 (d, J= 7.6 Hz, 1H), 7.61 (s, 1H), 7.47 (d, J= 7.3 Hz, 2H), 7.38 (t, J= 7.6 Hz, 2H), 7.30 (t, J= 7.2 Hz, 1H), 7.17 (d, J= 7.3 Hz, 1H), 6.96 (d, J= 8.4 Hz, 1H), 6.81 (d, J= 7.7 Hz, 1H), 5.13 (s, 2H), 4.39 (d, J= 6.5 Hz, 1H), 3.99 - 3.85 (m, 1H), 3.56 (s, 3H), 2.98 - 2.77 (m, 2H), 1.35 (s, 8H), 1.10 (d, J= 7.1 Hz, 3H). MS (ESI, m/z): 583 (M *). (S)-methyl-3-(4-(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-((S)-2 ((tert-butoxycarbonyl)amino)propanamido)propanoate (A12): To a 1000 L reactor, were added DMSO (460 kg, 7.5 w), All (61 kg, 104.7 mol, equiv.), bis(pinacolato)diboron (39.9 kg, 157.1 mol, 1.5 equiv.) and KOAc (41.1 kg, 418.9 mol, 4 equiv.). The mixture was degassed with N 2 for 5 times. Pd(dppf)C12 (5.75 kg, 7.9 mol, 0.075 equiv.) was added under N 2 and the mixture was degassed/refilled with N 2 for 5 times. The resulting mixture was heated to 60-90
C and stirred for -3 hrs. Upon the rxn completion, the reaction mixture was cooled to 25-30 °C and quenched into a mixture of water (610 kg, 10 w) & MTBE (670 kg, 11 w). The mixture was filtered through a diatomite pad (25 kg). The phases (the filtrate) were separated and the aqueous was extracted with MTBE (115 kg, 1.9 w). The combined MTBE extracts were dried over anhydrous Na 2SO 4 (50 kg) for 1 hr. before filtration. The cake was rinsed with MTBE (30 kg, 0.5 w) and the combined filtrate was concentrated under vacuum at 25-40 0C to afford 407 kg of MTBE solution which was used for next step directly. (S)-methyl 2-((S)-2-aminopropanamido)-3-(4-(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2 dioxaborolan-2-yl)phenyl)propanoate (A13): To a 1000 L reactor, was added MeOH (214 kg, 1.7 w of Al1) and cooled to -10-0 °C under N 2
. Gaseous HCl (123.4 kg, 1.0 w) was charged below 0 °C over 20 hrs. To another 2000 L reactor, was added the A12/TBME solution (784 kg, from 122 kg of Al1). The HCl/MeOH solution (337 kg) obtained above was added slowly at 15-25 °C over 2.5 hrs. (evolution of gas). The resulting solution was stirred at 15-25 °C for 2 hrs. Upon the rxn completion, the mixture was concentrated under vacuum at 2045 °C to - 350-400 kgs residue (-3 w of Al1). ACN (190 kg, 1.6 w of Al) was added and the mixture was distilled at 30-45 °C under vacuum until solids began to precipitate out. More ACN (920 kg, 7,5 w of All) was added. The mixture was cooled to 10-20 °C and stirred for 1 h. The slurry was filtered and the cake was rinsed with ACN (60 kg). The wet product was dried at 30-45 °C under vacuum for 24 hrs. to give 84.3 kg of A13-HC/A14-HCI as a light brown solid with 97.7 A% purity (34.3 A% of A13-HCI & 63.4 A% of A14-HCl) & 73.5 w% (by qNMR) in 77.3% yield (uncorrected) over 2 steps from 122 kg of A12. 1 H NMR (400 MHz; DMSO; Me4Si), 6(ppm): 1H NMR (400 MHz, dmso) 6 8.99 (d, J= 7.4 Hz, 1H), 8.30 (s, 3H), 7.58 (d, J= 7.2 Hz, 2H), 7.52 (s, 3H), 7.43 - 7.31 (m, 7H), 7.27 (d, J= 7.1 Hz, 4H), 6.97 (d, J= 8.3 Hz, 1H), 5.08 (s, 2H), 4.37 (dd, J= 13.6, 8.1 Hz, 1H), 3.80 (s, 1H), 3.58 (s, 3H), 2.94 (ddd, J= 22.7, 13.9, 7.3 Hz, 2H), 2.05 (s, 1H), 1.35 (d, J= 7.0 Hz, 3H), 1.28 (s, 12H). (5-((S)-2-((S)-2-aminopropanamido)-3-methoxy-3-oxopropyl)-2-(benzyloxy)phenyl)boronic acid hydrochloride (A14): To a 500 L reactor, were added 2-MeTHF (70 kg, 1.7 w), water (72 kg, 1.8 w), and amixture of A13-HCI & A14-HCI (40 kg, 77.1 mol, 1 equiv., calculated as 100% S,S-A13 HC). Themixture was stirred for -15 min or until most of A13-HCI & A14-HCI was dissolved. NaIO 4 (20.6 kg, 96.4 mol, 1.25 equiv.) was added in 10 portions over 30 min at 10-15 °C and the suspension was stirred for additional 15 min. A HCl aqueous solution (4 w%, 7.4 kg, 0.105 eq.) was added slowly at 10-15 °C over 1.5 hrs. The mixture was warmed to 15-20 °C and stirred for 6 hrs (slightly exothermic). Upon the rxn completion, the mixture was filtered and the solid was rinsed with MeTHF (8 kg, 0.2 w). Aqueous NaHSO 3 solution (16 kg NaHSO 3 in 48 kg water) was added slowly to above combined filtrate below 15 °C over -0.5 hrs.(exothermic). The phases were separated and the aqueous was extracted with MeTHF (28 kg, 0.7 w). The MeTHF extracts were combined and washed with brine (16 kg NaCl in 64 kg water). The organic phase was dried over anhydrous Na 2SO4 (120 kg) for 2 hrs. before filtration. The cake was rinsed with MeTHF (30 kg, 0.75 w). The MeTHF solution obtained above was added slowly to TBME (460 kg, 11.5 w) over 2 hrs. with stirring at 10-15 C (solid was precipitated out upon the completion of adding MeTHF solution). The slurry was stirred at 10-15 C for additional 1 hr. before filtration. The wet product was dried at 5~15 C under vacuum for -72 hrs. to give -26 kg of A14-HCI as a light brown solid with 96 A% purity & 90 w% (by qNMR) in 77.2% yield (uncorrected). 1 H NMR (400 MHz; DMSO; Me4Si), 6 (ppm): 1H NMR (400 MHz, dmso) 6 8.90 (d, J= 7.3 Hz, 1H), 8.20 (s, 3H), 7.72 (s, 2H), 7.47 (dd, J= 9.1, 4.6 Hz, 3H), 7.40 (t, J= 7.5 Hz, 2H), 7.33 (t, J= 7.0 Hz, 1H), 7.27 (d, J= 8.3 Hz, 1H), 6.99 (d, J= 8.4 Hz, 1H), 5.15 (s, 2H), 4.43 (dd, J= 13.7, 7.9 Hz,1H), 3.83 (s, 1H), 3.61 (s, 3H), 2.94 (ddd, J= 22.9, 13.9, 7.2 Hz, 2H), 1.36 (d, J= 6.9 Hz, 3H). Example 3 Preparation of Methyl(4S,7S,10S)-26-(benzyloxy)-10-(((benzyloxy)carbonyl)(methylamino) 16-hydroxy-7-methyl-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenacyclodecaphane-4-carboxylate (A16) OH BnO
HO, IBCF, 1.22 eq + HO HO OMe NMM,3eq ~N OH 0~10 HN °C, 1 h N CIHH 2N, .O O Cbz 0 A5 Me A14 Bn HO, OH I OH B OH OBn 0.02 eq. Pd162, 1.05eq.KHCO 3 (S) H [ HN COOMe Cbzs N 25 AN CO 2 Me 25 vv MeCN water N (s H(f N Me 0 191e H A15 Cbz O A16
Scheme 2C The synthesis of Methyl(4S,7S,1OS)-26-(benzyloxy)-10-(((benzyloxy)carbonyl)(methyl)amino) 16-hydroxy-7-methyl-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenacyclodecaphane-4-carboxylate (A16) is illustrated in Scheme 2C. (2-(benzyloxy)-5-((5S,8S,11S)-5-(4-hydroxy-3-iodophenyl)-11-(methoxycarbonyl)-4,8 dimethyl-3,6,9-trioxo-1-phenyl-2-oxa-4,7,10-triazadodecan-12-yl)phenyl)boronic acid (A15): To a 500 L reactor, were added DMA (72 kg), THF (137 kg), A14-HCI (25.64 kg, 58.7 mol, 1 equiv.) & A5 (25.91 kg, 58.7 mol, 1 equiv.) with stirring under N 2. The mixture was cooled to <-10 C before NMM (17.8 kg, 176.1 mol, 3 equiv.) was added slowly over 10 min below -10°C (slightly exothermic). The mixture was further cooled to -20 to -15 C and a solution of IBCF (8.02 kg, 0.46 mol, 1 equiv.) in DMA/THF (48.2 kg/ 91.3 kg, 1.9 w/ 3.6 w of A14-HC) was added slowly over 9 hrs. at -20 to 15 C (exothermic). The mixture was stirred for 5min and a sample was taken for IPC on HPLC: 83.9 A% of SSS-10a and 0.9 A% of A14 remaining. To a 2000 L reactor, were added water (520 kg), Na 2 CO 3 (25.6 kg) & EA (230 kg). The mixture was pre-cooled to -5-0 C before use. The rxn mixture was added slowly to the mixture of aqueous Na 2CO 3 & EA below 0 C over 1 hr. Then, the resulting mixture was stirred for 20 min. before filtration. The phases (the filtrate) were separated. The organic phase was washed with aq
NH 4 Cl(64 kg NH 4 Cldissolve in 260 kgs of water), followed by brine for 3 times (50 kgs of NaCl dissolved in 250 kg water, each). The organic phase was dried over anhydrous Na 2SO 4 (30 kg). Filtered and the cake was rinsed with EA (30 kg). The Filtrate was concentrated under vacuum at 30-45 °C to -50 kgs residue (2-2.5 w of A14-HC). EtOH (20 kg) was added and the mixture was distilled under vacuum at 30-45 °C to -50 kg again (2-2.5 w of A14-HC). This operation was repeated twice (each with 20 kg EtOH) to remove EtOAc (GC: <5 A% of EA in the residue) (product began to be precipitated out during the 3 rd time concentration). More EtOH (51.3 kg, 2 w of A14-HC) was added. The mixture was heated to 60-65 °C and stirred for 3 hrs. (some solids was dissolved). Then, n-heptane (74 kg, 2.9 w of A14-HC) was added slowly over 1 hr. (during the addition, the internal temperature was dropped to 35-40 °C). The mixture was stirred for 0.5 h and the internal temperature was further cooled to 15-25 °C. More n-heptane (103 kg, 4 w of A14-HC) was added slowly over 1 hr. and the resulting mixture was stirred for 2 hrs.at 15-25 °C. The slurry was filtered and the cake was washed with EtOH/n-heptane (11 kg/36 kg). The wet cake was dried under vacuum at 30-45 °C for 8 hrs. to give 29.1 kgs of A15 as an off-white solid with 95.9 A% & 91.2 w% purity, 98.8 % de in 60.3% yield (uncorrected). H NMR (400 MHz; DMSO; Me4Si), 6 (ppm): 1H NMR (400 MHz, DMSO) 6 10.44 (s, 1H), 8.33 1
(dd, J= 12.1, 7.2 Hz, 2H), 7.71 (s, 2H), 7.54 - 7.28 (m, 12H), 7.24 (d, J= 7.5 Hz, 1H), 7.05 (d, J= 7.7 Hz, 1H), 6.95 (d, J= 8.4 Hz, 1H), 6.84 (d, J= 8.4 Hz, 1H), 5.75 (s, 1H), 5.11 (s, 4H), 4.36 (dt, J= 14.5, 7.2 Hz, 2H), 3.56 (s, 3H), 2.91 (ddd, J= 21.8, 13.7, 7.2 Hz, 2H), 2.62 (s, 3H), 1.17 (s, 3H). MS (ESI,m/z): 824 (M +). Methyl(4S,7S,1OS)-26-(benzyloxy)-10-(((benzyloxy)carbonyl)(methyl)amino)-16-hydroxy-7 methyl-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenacyclodecaphane-4-carboxylate (A16): To a flask, were charged A15 (300 g, 90.5 w%, 329.7 mmol, 1.0 equiv.), KHCO 3 (38.1 g, 380 mmol, 1.15 equiv.) and Pd-162 (chloro(crotyl)(tri-tert-butylphosphine)palladium(II), CAS# 1334497-00-5) (3 g, 7.2 mmol, 0.02 equiv.). The rxn vessel was evacuated and backfilled with N 2 (5 min x 3). Acetonitrile (7.5 L, 25 v) and DI water (7.5 L, 25 v) (acetonitrile & DI water evacuated and backfilled with N 2 10min x 3 times respectively in advance) were added under N2 .The vessel containing the rxn mixture was again evacuated and backfilled with N 2 (15 min). The mixture was heated to 65 °C over -1 h and stirred for additional 1.5 h or until the completion of the reaction (A15: < 1.0 A% on HPLC). The rxn mixture was cooled to ambient temperature and diluted with DCM (27 v, 8 L). The phases were separated and the aqueous was extracted with DCM (-8 v, 2 L). The combined organic phase was dried with Na 2SO4 (300 g, 1 w) for 20 min. Filtered and the cake was washed with DCM (2 L). The combined filtrate and wash was concentrated under vacuum at 45 °C to afford crude A16 (-250 g) as a brown solid with 85 A% LC purity. The crude solid was used for next step without any further purification. 1 H NMR(400 MHz; DMSO; Me 4Si), 6(ppm): 9.31 (1 H, d, J= 4 Hz), 9.09 (1 H, t, J= 8 Hz), 8.51 8.41 (1 H, dd, J= 22 Hz) 7.44-6.68 (16 H, m), 5.97 (1 H, d, J= 4 Hz), 5.16-5.12 (4 H, m), 4.84-4.82 (1 H, m), 4.72-4.77 (1 H, m), 3.37 (3 H, t, J= 8 H), 3.31-3.27 (1 H, m), 3.05-2.98 (1 H, m), 2.64-2.60 (3 H, d, J=16 Hz), 1.20- 1.15 (3 H, m) MS (ESI, m/z): 652 (M).
Example 4 Alternate preparation of Methyl(4S,7S,1OS)-26-(benzyloxy)-10 (((benzyloxy)carbonyl)(methyl)amino)-16-hydroxy-7-methyl-6,9-dioxo-5,8-diaza-1,2(1,3) dibenzenacyclodecaphane-4-carboxylate (A16) BnO OH Bn I I 0 0 0 ROH O~ HN OMe + Pd-162/K 3 PO 4 H N 0 Me HN I H_ BocHN O OH THF/H 20 NHBoc N 60-65°C Me A14 Cbz O A5 N OH Cbz O A17
Bn Bn I 0 0 0 0 OH O OH HCI/DCM N Me PyBOP/NMM 10-15°C H NNH DMF 2 10-15°C HN CO 2Me OH HCI CbzN O N A18 Cbz O Me 0 Me A16
Scheme 2D Scheme 2D illustrates an alternate route to synthesis of Methyl(4S,7S,1OS)-26-(benzyloxy)-10 (((benzyloxy)carbonyl)(methyl)amino)-16-hydroxy-7-methyl-6,9-dioxo-5,8-diaza-1,2(1,3) dibenzenacyclodecaphane-4-carboxylate (A16) 3-{6-Benzyloxy-5'-[(benzyloxycarbonyl-methyl-amino)-carboxy-methyl]-2'-hydroxy biphenyl-3-yl}-2-(2-tert-butoxycarbonylamino-propionylamino)-propionic acid methyl ester (SSS E24c): To a flask (5 L) were added A12 (100.0 g, 226.8 mmol, 1.0 equiv), A13/A14 (130.0 g, 223.3 mmol, 0.98 equiv.), Pd-162 (5.7 g, 13.6 mmol, 0.06 equiv) and K 3PO4 (48.1g, 226.8 mmol, 1.0 equiv.) under N 2. A mixture of THF & H 20 (1/1, 3 L, sparged with nitrogen for at least 15min. before use) was then added under stirring. The solution was purged under vacuum and back-filled with nitrogen and repeated for three times. The reaction mixture was heated to 60-65°C and stirred for 2 hrs. Upon the completion of the reaction (IPC by HPLC), the mixture was extracted with EtOAc (3 x 600 mL) and the combined organic phase was washed with 5% aq. Na 2CO 3 (600mL), IM HCl (aq. 600 mL) and then brine (600 mL x 2). The organic phase was dried over Na 2SO 4 (100 g) and then filtered. The filtrate was concentrated under reduced pressure at 45 C to dryness. The solid obtained was slurried in a mixture of CH 2Cl 2 & petroleum ether (1/2, 700 mL) for 1h. Filtered and the cake was dried under high vacuum at-55 C for 4 h. It afforded the title compound A17 as a white solid (148.5 g, 0.193 mol, 98 A% HPLC purity, 85% isolated yield).
H NMR (400 MHz; DMSO; Me4Si), 6 (ppm): 9.23 (1H, s), 8.13 (1H, d, J=8 Hz), 7.35 - 6.79 (17 H, m), 5.45 (1 H, d, J= 24 Hz), 5.06-5.02 (4 H, m), 4.44-4.41 (1 H, m), 3.99 - 3.95 (1 H, m), 3.56 (3 H,s), 2.93 (2 H,m), 2.66 - 2.61 (3 H,d, J=20 Hz), 1.35 (9 H,s),1.12 (3 H,d, J=4 Hz). MS (E,m/z): 770 (M). 2-(2-Amino-propionylamino)-3-{6-benzyloxy-5'-[(benzyloxycarbonyl-methyl-amino) carboxy-methyl]-2'-hydroxy-biphenyl-3-yl}-propionic acid methyl ester (A18) To a DCM solution (1.95 L, 15 vol) of A17 (130.0 g, 168.8 mmol, 1.0 equiv), was bubbled HC (gas) at 10-15 C for3hrs. Upon the completion of the reaction (IPC by HPLC), the mixture was concentrated under vacuum at 25 Cfor 3 hrs. The solid was dissolved in DCM (600 mL) under stirring. TBME (1200 mL) was the added dropwise into the above solution in a period of -10 min. The slurry was filtered and the cake was dried under high vacuum at -30-35 C for 10 h to afford the title compound SSS A18 (108 g, 0.153 mol, 96.6 A% HPLC purity, 95.5% isolated yield) as a yellow solid. 1 H NMR (400 MHz; DMSO; Me4Si), 6(ppm): 13.00 (1 H, brs), 9.67 (1 H,s), 8.95 (1 H, d, J= 8 Hz), 8.24 (1 H,s) 7.36-6.97 (16 H, m), 5.76-5.71 (1 H, m), 5.11 (2 H, d, J= 4 Hz), 5.03 (2 H, s), 4.46-4.44 (1 H, m), 3.84 (1 H, m), 3.61 (3 H, s), 3.04-3.00 (1 H, m), 2.96-2.90 (1 H, m), 2.59-2.55 (3 H,d, J=16 Hz), 1.36 (3 H,d,J=4 Hz). MS (El, m/z): 670 (M *). 3-Benzyloxy-14-(benzyloxycarbonyl-methyl-amino)-18-hydroxy-11-methyl-10,13-dioxo-9,12 diaza-tricyclo[13.3.1.12,6]icosa-1(18),2(20),3,5,15(19),16-hexaene-8-carboxylic acid methyl ester (A16) A solution of PyBOP (11.0 g, 2.12 mol, 1.5 equiv) & NMM (4.3 g, 4.25 mmol, 3.0 equiv.) in DMF (100 mL, 10 vol) was stirred at 40-45C. The DMF solution (100 mL, 10 vol) of A18 (10.0 g, 1.41 mol, 1.0 equiv) was added dropwise to the above solution at 10-15 Cin a period of 4 hrs. The mixture was stirred at 10-15C for 0.5 hrs. The rxn was poured into water (800 mL), the precipitate was filtered. The solid was dissolved in EtOAc (200 mL) and the solution was consecutively washed with 0.1M HC (10mL), 5% NaHCO3 (100 mL), 0.1M HCl (100 mL) and brine (100 mL x 2). The organic phase was dried over anhydrous Na 2SO4 (-10 g) and filtered. The filtrate was concentrated under reduced pressure at 35-40 C to afford A16 (10.7 g, 84 A% HPLC purity, 48w% by qNMR, 71% yield) as a yellow solid. 1 H NMR(400 MHz; DMSO; Me 4Si), 6(ppm): 9.31 (1 H, d, J= 4 Hz), 9.09 (1 H, t, J= 8 Hz), 8.51 8.41 (1 H, dd, J= 22 Hz) 7.44-6.68 (16 H, m), 5.97 (1 H, d, J= 4 Hz), 5.16-5.12 (4 H, m), 4.84-4.82 (1 H, m), 4.72-4.77 (1 H, m), 3.37 (3 H, t, J= 8 H), 3.31-3.27 (1 H, m), 3.05-2.98 (1 H, m), 2.64-2.60 (3 H, d, J=16 Hz), 1.20- 1.15 (3 H, m). MS (El, m/z): 652 (M *). Example 5 Preparation of ((tert-butoxycarbonyl)amino)ethoxy) 26-hydroxy-7-methyl-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenacyclodecaphane-4-carboxylate (A23) and subsequent compounds
Bn BocHN Bn 0 I OH BocHN 0 (5 eq.) (S) 5 eq. K 3 PO4 | (S) H 2 , Pd/C 0.2 w H HN COOMe 5 v DMA HN COOMe DMA, 10v (S) N 50°C for 3 h N O( CbzO A16 C A19 CbzO0
BocHN BocHN
HO mo HO OO HN OH 0H BocHNN/2 A21
(S) H s COOMe HATUDIPEA H 0 H HN N ( A20 THF25 Fmo' Emoc N N. N .,O Me 0 Me A22 NHBoc BocHN
HO R C)m Xd OH
0 \N____) TBAF 0 H HN O _ THF, 25 C H2N N N ,O 0 HOAt, EDCI
Me 0 !e THF, 25 °C, NMM
NHBoc A23 BocHN
BocHN 0 HO
CN HO Rb m Rb '7)m 0 NH HHH i>pd) 1 X2 ,
RO X H 0 H HN N0O NH X2 1. LiOH O Me O Me N O 2.H 2 NCH2 CN A25 O - Me 0 Me HATU, DIPEA NH 2 A24 3. MSA NHBoc Scheme 2E The synthesis of ((tert-butoxycarbonyl)amino)ethoxy)-26-hydroxy-7-methyl-6,9-dioxo-5,8-diaza
1,2(1,3)-dibenzenacyclodecaphane-4-carboxylate (A23) and subsequent compounds is illustrated in Scheme 2D. Methyl(4S,7S,1OS)-26-(benzyloxy)-10-(((benzyloxy)carbonyl)(methyl)amino)-16-(2-((tert butoxycarbonyl)amino)ethoxy)-7-methyl-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenacyclodecaphane-4
carboxylate (A19): To a rxn vessel, were added the DMA solution (9 L, 6 v related to A16) of the crude A16 (1.5 kg, the assay of A16 was calculated based on the qNMR of A15 and assumed the conversion from A15 to A16
to be 100%), K 3PO4 (2.1 kg, 5.0 equiv.) and 2-bromoethane(Boc)amine (2.2 kg, 5.0 equiv.). The rxn mixture was heated to 50 C over -1 h and stirred for additional 3 hrs. or until the reaction completion (0.25 A% of A16 remained on HPLC). After cooling the rxn mixture gradually to -15 C, the rxn mixture was diluted with EtOAc (45 L, 25 v related to A15) & 30 L of ID water. The phases were separated and the organic phase was washed with 10% brine (9 L x 3, standing for -1 h for each time). The filtrate and wash were combined and dried with 1.5 kg of anhydrous Na 2SO 4 for 30 min with stirring. Filtered and the cake was washed with EtOAc (2 L), the combined filtrate was concentrated under vacuum at 45 C for -3 h to afford an oil. Slurrying the oil in MeOH/EA/MTBE (3.75 L/1.5 L/3 L) at 10-20°C for 20 h afforded a white solid. Filtered and the cake was washed with MeOH (200 mL), the wet cake was dried under vacuum at 40-50 °C for 4 h to afford 580 g of A19 with 98.8 A% LC purity in 37% overall yield (uncorrected) over two steps from 1.8 kg of A15 (90.5 w%). 1 H NMR (400 MHz, dmso) 69.15 - 8.97 (m, 1H), 8.46 (dd, J= 23.5,9.0 Hz, 1H), 7.21 (dddd, J= 70.5, 41.8, 17.2, 8.3 Hz, 14H), 6.74 - 6.61 (m, 2H), 5.99 (d, J= 4.8 Hz, 1H), 5.27 - 5.07 (m, 4H), 4.87 (s, 1H), 4.77 - 4.65 (m, 1H), 4.08 - 3.90 (m, 2H), 3.68 (s, 3H), 3.30 (d, J= 21.4 Hz, 1H), 3.19 (s, 2H), 3.06 2.91 (m, 1H), 2.60 (d, J= 14.3 Hz, 3H), 1.36 (d, J= 17.6 Hz, 9H), 1.16 (dd, J= 10.5, 6.9 Hz, 3H). Methyl(4S,7S,1OS)-16-(2-((tert-butoxycarbonyl)amino)ethoxy)-26-hydroxy-7-methy-10 (methylamino)-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenacyclodecaphane-4-carboxylate (A20): To a flask, were charged DMA (2 L, 10 v), A19 (200 g, >98 A%), 10% Pd/C (40 g, 0.2 w). The vessel containing the rxn mixture was evacuated and backfilled with H 2 (5 min x 3). The mixture was stirred under H2 at 50 C for 16 h or until the rxn completion (97.8 A% of A15 and no A19 remained). The rxn mixture was cooled to ambient temperature and diluted with 4 L of EtOAc. The resulting mixture was washed with brine (2 L x 4) and the organic phase was dried with 400 g of anhydrous Na 2SO 4 for 10 min. Filtered and the cake was washed with EtOAc (2 L), the combined filtrate was concentrated under vacuum at 45 °C for 3 h to afford 132 g of desired product as light yellowish solid with 98.2 A% LC purity (major impurity 1.2 A% @ 15.5 min on HPLC). The crudeA20 (98.2 A%) was dissolved in 2 v of i-propanol at -40 C to afford a gel- like solution and the solution was continuously stirred for -1 h at 50 C to afford a large amount of nice free-flowing white solid. About 16 v of n-heptane was then added dropwise at 3050 °C in a period of 1.5 h. The resulting suspension was cooled with ice water to <20 °C in a period of -40 mins. The suspension was filtered and the cake was washed with 200 mL of n-heptane. The wet solid was dried under vacuum at 50 C for 4 h to afford 115 g of A20 as an off-white solid with 98.4 A% LC purity (major impurity @ 15.5 min, 0.85 A%) in 80% yield (uncorrected). 1 H NMR (400 MHz, dmso) 69.01 (d, J= 8.8 Hz, 1H), 8.71 (s, 1H), 8.54 (d, J= 8.8 Hz, 1H), 7.35 (dd, J= 8.5, 1.9 Hz, 1H), 7.02 (dd, J= 8.3, 2.2 Hz, 1H), 6.95 (d, J= 8.6 Hz, 2H), 6.88 (s, 1H), 6.74 (d, J= 8.1 Hz, 2H), 4.78 - 4.66 (m, 1H), 4.48 (t, J= 9.7 Hz, 1H), 4.36 (s, 1H), 3.99 (t, J= 6.2 Hz, 2H), 3.70 (s, 3H), 3.22 (q, J= 6.0 Hz, 2H), 2.98 (d, J= 14.4 Hz, 1H), 2.90 - 2.74 (m,1H), 2.29 (s, 3H), 2.12 (s, 1H), 1.36 (s, 9H), 1.22 (d, J= 6.8 Hz, 3H). Methyl (4S,7S,1OS)-10-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-((tert butoxycarbonyl)amino)-N-methylbutanamido)-16 (2-((tert-butoxycarbonyl)amino)ethoxy)-26-hydroxy-7-methyl-6,9-dioxo-5,8-diaza-1,2(1,3) dibenzenacyclodecaphane-4-carboxylate (A22). To a solution of Fmoc-DAB(Boc)-OH (A21) (16.0 g, 36.3 mmol) and A20 (20.73 g, 36.3 mmol, 1 equiv.) in THF (160 mL, 10 V) was added DIPEA (12.7 mL, 72.6 mmol, 2.00 equiv.), followed by HATU (14.09 g, 36.32 mmol, 1 equiv.) The reaction was stirred at 20 °C for 4 h. To the reaction mixture was added IPAc (80 mL, 5 V) followed by NaHCO 3 (5 wt%, 160 mL, 10 V). After the layers were completely separated. The both layers were separated and analyzed. The organic layer was washed with water (48 mL, 3 V). The organic layer was then concentrated and solvent switched to THF (3x10 V) at 50 °C and under vacuum at 350 mbar to Vtot 100 mL. At 60 °C, to the solution was slowly add MeCN (100 mL) and seed was introduced. Additional 100 mL of MeCN was slowly charged. The reaction was then cooled from 60 °C to 50 °C (3 h), then to 40 °C (2 h), and then to 25 °C. The solid was collected by filtrated and then washed with MeCN / THF (1:1) (70 mL), and with MeCN 3 times (90 mL + 70 mL + 60 mL). The white solid was then dried in the oven overnight (40 °C, vacuum). 28.1 g of A22 was obtained as a white solid (78% isolated yield). Methyl (4S,7S,1OS)-10-((S)-2-amino-4-((tert-butoxycarbonyl)amino)-N-methylbutanamido) 16-(2-((tert-butoxycarbonyl)amino)ethoxy) 26-hydroxy-7-methyl-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenacyclodecaphane-4-carboxylate (A23). To a solution of A22 (27.50 g, 27.70 mmol) in THF (275 mL, 10 V) was added TBAF (1.0 M in THF, 55 mL, 2 equiv.). The reaction was stirred at rt for 4 h. To the reaction mixture was added IPAc (38 mL, 1.4 V) and 10% aq K2HPO4 (192 mL, 7 V) and the layers were separated. The organic layer was treated with 10 wt% aq K 2HPO4 (190 mL, 7 V). After the phase cut, the organic layer was then treated with 20 wt% citric acid (275 mL, 10 V), DMA (27.5 mL, 1 V) and heptane (137.5 mL, 5 V) in this order while stirring. After the phase cut, the aqueous layer was then treated with heptane (137.5 mL, 5 V). After the phase cut, to the aqueous layer was added IPAc (275 mL, 10 V) followed by 30% K2 CO3 (175 mL, 6.4 V) to pH 9. After the phase cut, aqueous layer was washed 2 x 150 mL (5 V) of IPAc. The organic layers were combined and washed with 5 V of water. The organic solution of A23 was concentrated to 5 V and taken to the next step without further purification. Compound A24. To a 40 mL scintillation vial with stir bar was added (1.0 g, 1.297 mmol, 1 equiv) of A23, 1 equiv. of compound z, HOAt (216.2 mg, 1.557 mmol, 1.2 equiv), EDCI (497.4 mg, 2.594 mmol, 2 equiv). THF (10 mL) and NMM (0.296 mL, 2.594 mmol, 2.0 equiv) were added and themixture was stirred at ambient temperature. After 5 h, the reaction was diluted with water (10 mL), EtOAc (20 mL). The mixture was stirred vigorously and clarified. Separated phases, extracted organic phase with EtOAc (3 x 15 mL). Washed combined organic phases with 0.5 M aq HCl (2 x 10 mL). Washed combined organic phases with sat aq NaHCO 3 (2 x 10 mL). Washed combined organic phases with water (10 mL) and brine (10 mL). After concentration, the solid was dissolved in EtOAc (5 mL) and heptane was added dropwise to give a white suspension. Some gummy tan clumps clung together and had to be broke up with spatula, sonicated to give a more uniform suspension and stirred at 400 rpm overnight. The solid was collected through a filtration and dried at rt (vacuum oven) for 24 h. to give A24 as a white solid. Compound A25 To a 40 mL scintillation vial with stir bar was added A24 (1 equiv), and THF (22 mL). After dissolution, the reaction was cooled to 0 °C. To the solution was charged 1 M aqLiOH solution dropwise to control internal temperature < 1.5 °C. The reaction was monitored by HPLC. After >99% conversion around 1 h, the reaction was quenched with EtOAc (20 mL) and 5% brine. After the phase cut, the organic layer was acidified wht 1 M aqu HCl (6.4 mL) to pH 3-4. After the phase cut, the aqueous layer was washed with EtOAc (2x 25 mL). The organic phase was combined and concentrated under reduced pressure. The resulting crude carboxylate (not shown in Scheme 2E) was was loaded into a 100m easy max reactor followed by dry MeTHF (40ml (8 vol) and the mixture was allowed to stir at 25 °C until obtaining a clear solution. HATU (1.1 equiv.) was then added to the mixture and the slurry was stirred at 25 °C for 60 minutes. A separate solution of aminoacetonitrile was prepared by dissolving aminoacetonitrile HCl (1.1 equiv.) in DMF (5.0ml 1 vol) followed by the addition of DIPEA (2.2 equiv.) and stirring for 30 minutes at 25 °C. The aminoacetonitrile DMF solution was then added to the easy max reactor at 25 °C and the resulting mixture was allowed to stir for 60minutes until completion. To the completed reaction was added a 2.5% NaHCO3 solution in H20 (5 vol) followed by MeTHF (5 vol). The resulting mixture was separated and the organics were washed with H 20 (5 vol) twice. The resulting organic solution was filtered through a celite pad and concentrated to dryness. The crude product was dissolved in DMF (50ml, 10 vol) and heated to 70 °C. H20 (30l, 6 vol) was added and mixture was allowed to stir for 15 minutes and cooled to 20 °C over 14h. The resulting slurry was filtered and washed with H 20 (2vol) followed by heptane (2vol) then dried in vacuo at 40 °C for 16h to give the glycine nitrile warhead compound as a white solid, which was dissolved in THF and stirred at 25 °C until fully dissolved. To this mixture was added methanesulfonic acid (6.2 uL, 2 equiv.) and the resulting mixture was heated to 60 °C and stirred for 20 h. White solid precipitated and was collected by filtration.to give A25. Compounds of formula A25 prepared by the above methods are shown below in Table 1 together 1 with H NMR data.
Table 1
H 2N
N O HN NI-CN 0 N0 Ns N O( O, 0O-O
NH 2
1 H NMR (400MHz, MeOH-d4) 68.49 (brs, 1H), 8.19 (d, J=8.0 Hz, 2H), 7.23 (d, J=8.0 Hz, 2H), 6.99-6.83 (m, 5H), 6.62 (s, 1H), 6.51 (s, 1H), 5.34-5.24 (m, 1H), 4.82-4.68 (m, 2H), 4.50-4.35 (m, 3H),
4.25 (s, 2H), 3.42 (s, 2H), 3.14 (t, J=7.2 Hz, 2H), 3.01 (s, 3H), 2.95-2.80 (m, 2H), 2.44 (s, 6H), 2.33-2.25 (m, 1H), 2.22-2.09 (m, 1H), 1.38-1.33 (m, 9H)
H2N _,jO
H ~. NH2 HN NyCN
0 O 0 0
NH 2
H NMR (400MHz, MeOH-d4) 68.48 (brs, 1H), 7.73 (d, J=8.0 Hz, 2H), 7.65 (d, J=8.0 Hz, 2H), 7.35 (d, J=7.2 Hz, 1H), 7.18-7.09 (m, 2H), 7.03 (s, 1H), 6.97 (s, 1H), 6.91 (d, J=8.4 Hz, 1H), 6.80 (s, 1H), 6.47 (s, 1H), 5.12-5.09 (m, 1H), 4.85-4.70 (m, 2H), 4.43-4.33 (m, 2H), 4.21 (s, 2H), 3.62-3.43 (m, 2H), 3.26-3.09 (m, 4H), 3.00 (s, 3H), 2.61 (s, 3H), 2.29-2.19 (m, 2H), 1.45 (s, 9H), 1.43 (d, J=7.2 Hz, 3H)
H2N _,,,4O
H N~ OH 0 N CN HN NH NNOON H, 0 0
NH 2
H NMR (400MHz, MeOH-d4) 6 8.51 (brs, 2H), 7.90-7.60 (m, 4H), 7.31-7.24 (m, 3H), 7.15 (d, J=8.0 Hz, 1H), 7.10 (d, J=8.0 Hz, 1H), 6.90-6.80 (m, 2H), 6.70-6.45 (m, 2H), 5.19-5.16 (m,1H), 4.82-4.59 (m, 2H), 4.40-4.28 (m, 2H), 4.20 (s, 2H), 3.36-3.32 (m, 1H) 3.27-3.24 (m, 1H), 3.15-2.96 (m, 7H), 2.65 (s, 3H), 2.55 (d, J=8.0 Hz, 2H), 2.33-2.24 (m, 1H), 2.21-2.14 (m, 1H), 1.95-1.87 (m, 1H), 1.35 (d, J=6.8 Hz, 3H), 0.94 (d, J=6.8 Hz, 6H)
CA ~ H2N,^ 0HO I C 4 He N O HN.C NN ,CN N N- N 0 HN
0 0
NH 2
H NMR (400MHz, MeOH-d4) 68.77 (s, 1H), 8.53 (brs, 2H), 8.25 (d, J=7.5 Hz, 2H), 7.33-7.27 (m, 3H), 7.14 (d, J=8.0 Hz, 1H), 7.00 (d, J=8.0 Hz, 1H), 6.91-6.83 (m, 2H), 6.59 (s, 1H), 6.54 (s, 1H), 5.21-5.15 (m, 1H), 4.83-4.80 (m, 1H), 4.74-4.69 (m, 1H), 4.39-4.29 (m, 2H), 4.22 (s, 2H), 3.29-2.99 (m, 6H), 2.96 (s, 3H), 2.71 (t, J=7.6 Hz, 2H), 2.64 (s, 3H), 2.35-2.25 (m,1H), 2.22-2.14 (m,1H), 1.73-1.61 (m, 2H), 1.46-1.32 (m, 5H), 0.98 (t, J=7.4 Hz, 3H).
H2 N HO
CN HN NyCN
N N 0
O O~ NH 2
H NMR (400MHz, MeOH-d4) 68.77 (s, 1H), 8.53 (brs, 1H), 8.27 (d, J=8.0 Hz, 2H), 7.35-7.26 (m, 3H), 7.14 (d, J=8.8 Hz, 1H), 7.04-6.97 (m, 1H), 6.93-6.87 (m, 1H), 6.84 (d, J=8.4 Hz, 1H), 6.62 (s, 1H), 6.52 (s, 1H), 5.22-5.15 (m, 1H), 4.84-4.69 (m, 2H), 4.37-4.25 (m, 2H), 4.22 (s, 2H), 3.50-2.93 (m, 8H), 2.70 (t, J=7.6 Hz, 2H), 2.40 (s, 3H), 2.33-2.18 (m,1H), 2.18-2.05 (m,1H), 1.74-1.62 (m, 2H),1.40
1.35 (m, 9H), 0.93 (t, J=6.8 Hz, 3H).
H2N,_,, HO
C2 H 5 NN H
NH 2
H NMR (400MHz, MeOH-d4) 68.76 (s, 1H), 8.23 (d, J=8.0 Hz, 2H), 7.36-7.25 (m, 3H), 7.13 (d, J=8.8 Hz, 1H), 6.90-6.89 (m, 2H), 6.79 (d, J=7.2 Hz, 1H), 6.65 (s, 1H), 6.51 (s, 1H), 5.15-5.12 (m, 1H), 4.81-4.79 (m, 1H), 4.67-4.59 (m, 1H), 4.24 (s, 2H), 4.20-4.05 (m, 2H), 3.10-2.80 (m, 6H), 3.00 (s, 3H), 2.73 (q, J=7.2 Hz, 2H), 2.60 (s, 3H), 2.15-2.00 (m, 1H), 2.00-1.85 (m, 1H), 1.35 (d, J=7.2 Hz, 3H), 1.28 (t, J=7.2 Hz, 3H).
H 2N HO
C2 H 5 N .N
N - - 0 N HN CN o O 0 NH 2
H NMR (400MHz, MeOH-d4) 68.48 (brs, 2H), 8.21 (d, J=7.2 Hz, 2H), 7.29 (d, J=7.6 Hz, 2H), 7.20 (brs, 2H), 7.00-6.82 (m, 3H), 6.58 (brs, 2H), 5.32-5.27 (m, 1H), 4.85-4.75 (m, 2H), 4.50-4.40 (m, 2H), 4.24 (s, 2H), 3.50-3.30 (m, 2H), 3.20-3.05 (m, 2H), 3.00-2.85 (m, 5H), 2.70 (q, J=7.6 Hz, 2H), 2.48 (s, 6H), 2.35-2.20 (m, 1H), 2.20-2.05 (m, 1H), 1.35 (d, J=6.4 Hz, 3H), 1.29 (t, J=7.2 Hz, 3H).
H2N OH O
N 0 0 -N HN O O
NH 2
H NMR (400MHz, MeOH-d4) 68.13 (d, J=8.0 Hz, 2H), 7.26 (s, 2H), 6.94-6.86 (m, 5H), 6.73 (s, 1H), 6.37 (s, 1H), 5.38-5.34 (m, 1H), 4.83-4.78 (m, 1H), 4.56-4.53 (m,1H), 4.47-4.43 (m, 1H), 4.29-4.21 (m, 3H), 4.08 (t, J=6.4 Hz, 2H), 3.50-3.35 (m, 2H), 3.20-3.05 (m, 2H), 3.02 (s, 3H), 2.95-2.88 (m, 1H), 2.80-2.60 (m, 1H), 2.33 (s, 6H), 2.33-2.20 (m, 1H), 2.20-2.10 (m, 1H), 1.89-1.82 (m, 2H), 1.50-1.40 (m, 4H), 1.36 (d, J=6.8 Hz, 3H), 1.01 (t, J=7.2 Hz, 3H).
H 2 N,_,,oHO
C5 H1 1 NOH N C H N ON N 'sN 0 HN H 0i O o
NH2
H NMR (400MHz, MeOH-d4) 6 8.52 (brs, 1H), 8.23 (d, J=8.0 Hz, 2H), 7.32-7.26 (m, 3H), 7.21 (d, J=8.0 Hz, 1H), 6.98 (brs, 1H), 6.92-6.85 (m, 3H), 6.59 (brs, 2H), 5.30-5.28 (m, 1H), 4.84-4.82 (m, 2H), 4.46-4.39 (m, 2H), 4.25 (s, 2H), 3.42-3.37 (m, 2H), 3.16 (t, J=8.0 Hz, 2H), 3.05-2.95 (m, 2H), 3.02 (s, 3H), 2.71 (t, J=8.OHz, 2H), 2.51 (s, 6H), 2.34-2.20 (m, 1H), 2.20-2.05 (m, 1H), 1.70 (t, J=6.8 Hz, 2H), 1.50 1.35 (m, 7H), 0.96 (t, J=6.4Hz, 3H).
H2N OHO,,
Ns N 0 O 0
NH 2
H NMR (400MHz, MeOH-d4) 68.76 (s, 1H), 8.51 (brs, 1H), 8.19 (d, J=8.4 Hz, 2H), 7.49 (d, J=8.4 Hz, 2H), 7.27 (d, J=8.4 Hz, 1H), 7.16 (d, J=8.4 Hz, 1H), 6.93-6.87 (m,1H), 6.85-6.82 (m, 2H), 6.64 (s, 1H), 6.44 (s, 1H), 5.20-5.17 (m, 1H), 4.81-4.78 (m, 1H), 4.65-4.59 (m, 1H), 4.44-4.32 (m, 2H), 4.24 (s, 2H), 3.41-3.30 (m, 2H), 3.16 (t, J=7.6 Hz, 2H), 3.00-2.90 (m, 2H), 2.96 (s, 3H), 2.591 (s, 3H), 2.33-2.13 (m, 2H), 1.38 (s, 9H), 1.35 (d, J=6.8 Hz, 3H).
H2N OHO,,
H N ON H~ 0 HN
H 00
NH 2
H NMR (400MHz, MeOH-d4) 68.62 (s, 1H), 8.50 (brs, 1H), 7.69 (d, J=8.0 Hz, 2H), 7.60 (s, 1H), 7.30-7.17 (m, 4H), 6.89-6.82 (m, 3H), 6.70 (s, 1H), 6.31 (s, 1H), 5.21-5.18 (m,1H), 4.81-4.76 (m, 2H), 4.48-4.35 (m, 2H), 4.26 (s, 2H), 3.45-3.38 (m,2H), 3.23-3.15(m, 2H), 3.05-2.84 (m, 2H), 2.98 (s, 3H), 2.55 (d, J=7.2 Hz, 2H), 2.35 (brs, 2H), 2.29-2.19 (m, 2H), 1.96-1.89 (m, 1H), 1.35 (d, J=6.8 Hz, 3H), 0.95 (d, J=6.8 Hz, 6H).
H 2N ,HO -.
H NN OCN 0 HHN H 0 o o
NH 2
H NMR (400MHz, MeOH-d4) 68.52 (s, 1H), 7.82 (d, J=7.6 Hz, 2H), 7.72 (d, J=8.0 Hz, 1H), 7.64 (d, J=8.0 Hz, 1H), 7.50 (d, J=8.4 Hz, 2H), 7.33-7.27 (m, 1H), 7.17 (d, J=8.4 Hz, 1H), 7.00 (d, J=8.0 Hz, 1H), 6.91-6.85 (m, 2H), 6.57 (brs, 2H), 5.21-5.17 (m, 1H), 4.85-4.80 (m, 1H), 4.63-4.59 (m, 1H), 4.41 4.32 (m, 2H), 4.21 (s, 2H), 3.28-3.00 (m, 6H), 2.97 (s, 3H), 2.66 (s, 3H), 2.32-2.25 (m,1H), 2.21-2.14 (m, 1H), 1.42 (s, 9H), 1.36 (m, 12H).
H2N 1NHO
0 Hi NNN
NH 2
H NMR (500 MHz, DMSO-d6) 69.17 (d, J =7.3 Hz, 1H), 8.98 (d, J= 7.7 Hz, 1H), 8.71 (t, J =5.5 Hz, 1H), 8.44 (d, J = 9.0 Hz, 1H), 8.36 - 8.29 (m, 2H), 7.59 - 7.52 (m, 2H), 7.19 - 7.04 (m, 3H), 6.90 - 6.80 (m, 2H), 6.71 (s, 1H), 6.42 (s, 1H), 5.09 - 5.01 (m, 1H), 4.80 - 4.66 (m, 2H), 4.29 - 4.15 (m, 4H), 3.19 3.09 (m, 3H), 3.02 - 2.88 (m, 6H), 2.50 (s, 6H), 2.14 - 2.03 (m, 1H), 2.02 - 1.91 (m, 1H), 1.35 (s, 9H), 1.21 (d, J = 6.6 Hz, 3H).
H2 N
H NN OCN 50 0 HN
H z O 0 00
NH 2
H NMR (400MHz, MeOH-d4) 68.47 (brs, 3H), 7.67 (brs, 2H), 7.54 (d, J=7.6 Hz, 2H), 7.38 (brs, 1H), 7.24 (s, 2H), 7.00-6.75 (m, 3H), 6.89 (s, 1H), 6.36 (brs, 1H), 5.38-5.30 (m, 1H), 4.85-4.75 (m, 1H), 4.60-4.47 (m, 1H), 4.45-4.35 (m, 1H), 4.30-4.20 (m, 1H), 4.24 (s, 2H), 3.50-3.40 (m, 2H), 3.20-3.10 (m, 2H), 3.01 (s, 3H), 2.90 2.80 (m, 1H), 2.54 (s, 3H), 2.40-2.00 (m, 6H), 1.42 (s, 9H), 1.34 (d, J=6.8 Hz, 3H).
H2 N OHO I
H _N O HN NIIICN N NNOOO 0IH
0 0Q NH 2
H NMR (400MHz, MeOH-d4) 68.77 (s, 1H), 8.51 (brs, 1H), 8.27 (d, J=8.4 Hz, 2H), 7.47 (d, J=8.0 Hz, 2H), 7.32-7.26 (m, 1H), 7.16 (d, J=8.4 Hz, 1H), 7.02-6.96 (m, 1H), 6.88 (brs, 1H), 6.85 (d, J=8.4 Hz, 1H), 6.56 (brs, 2H), 5.21-5.16 (m, 1H), 4.82-4.78 (m, 1H), 4.73-4.67 (m, 1H), 4.43-4.31 (m, 2H), 4.23 (s, 2H), 3.42-3.33 (m, 2H), 3.15 (t, J=7.6 Hz, 2H), 3.10-3.00 (m, 2H), 2.96 (s, 3H), 2.64 (s, 3H), 2.35 2.20 (m, 1H), 2.20-2.05 (m, 1H), 1.74 (q, J=7.2 Hz, 2H), 1.36 (d, J=6.8 Hz, 3H), 1.35 (s, 6H), 0.93 (t, J=7.2 Hz, 3H).
H2N ,-,4O
H N NH 2 HN N 1CN 0 HNI< Ns NN NO0 0 o
NH 2
H NMR (400MHz, MeOH-d4) 68.17 (d, J=8.4 Hz, 1H), 8.04 (d, J=8.4 Hz, 1H), 7.54-7.42 (m, 2H), 7.34-7.24 (m, 1H), 7.24-7.00 (m, 2H), 6.95-6.83 (m, 2H), 6.65 (s, 1H), 6.56 (brs, 1H), 5.18-5.06 (m, 1H), 4.83-4.73 (m, 2H), 4.53-4.32 (m, 2H), 4.24 (s, 2H), 3.45-3.33 (m, 2H), 3.22-3.11 (m, 2H), 3.07-2.87 (m, 1H), 3.00 (s, 3H), 2.86-2.67 (m, 1H), 2.46 (s, 3H), 2.32-2.05 (m, 2H), 1.44 (s, 9H), 1.36 (d, J=6.8 Hz, 3H). While the present invention has been described with reference to the specific embodiments thereof, it should be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process, process step or steps, to the objective spirit and scope of the present invention. All such modifications are intended to be within the scope of the claims appended hereto.
Text continues on page 56.
Other paragraphs of the invention as described herein are defined in the following paragraphs: Still further paragraphs are within the scope of the following paragraphs. 1. A method for making an arylomycin ring of formula o
4 5 Pg2 O0 5 OH R1 O R7
R2 R3 R6 (R) R HN
wherein: Y is halogen; R is: hydrogen; or CI 4alkyl; and may be the same or different on each occurrence; R, R2, R3, R4 , R' and R6 each independently is: hydrogen; C 4 alkyl; halo-C 4alkyl; halo; amino; amino-CI4alkyl; hydroxy; hydroxy-CI 6alkyl; cyano; cyano-C1.6alkyl; or nitro, wherein the amino and hydroxyl .0 moieties may optionally include a protecting group; R? is: hydrogen; or C 4 alkyl;
R 8 is: hydrogen; CI 4 alkyl; halo-CI 4 alkyl; halo; amino; amino-C1.4alkyl; hydroxy; hydroxy-C 6 alkyl; cyano; or cyano-C1.6alkyl, wherein the amino and hydroxyl moieties may optionally include a protecting group; Ra is: hydrogen; or CI 4alkyl; and may be the same or different on each occurrence, or two R groups .5 may form a C2 -6 alkylene that, together with the atoms to which they are attached, may form a five- or six membered ring; Pg' is an optional amine protecting group and may be the same or different on each occurrence; and Pg 2 is an optional hydroxyl protecting group and may be the same or different on each occurrence; the method comprising: .0 reacting a phenyl boronate compound of formula m: 2 4 Fg 0 5 RaOB 7 6 ORa R OR HN H 2N O O
R8 m or a salt or solvate thereof, with a phenyl halide compound of formula e;
OH R1 Y R2 R3
N OH Pg1 0 or a salt or solvate thereof, to form a compound of formula n;
OH Rao B'ORa Y R 6 OPg 2
R2 R R3 O R7 R4 H 1 R5 N N ROR Me O H O or a salt or solvate thereof; and treating the compound of formula n with chloro(crotyl)(tri-tert-butylphosphine)palladium(11), to make the compound of formula o; or a salt or solvate thereof.
2. A method of making an arylomycin ring of formula o
Pg 2 4
O1 5 R OHR7 R R7
R2 R3 R 6 (R) R HN
101 Pgi O Ra wherein: Y is halogen; R is: hydrogen; orCI 4alkyl; and may be the same or different on each occurrence, or two R groups may form aC2-6alkylene that, together with the atoms to which they are attached, may form a five- or six membered ring; R, R2, R3, R4, Rand R6 each independently is: hydrogen;C1. 4alkyl; halo-C 4alkyl; halo; amino; amino-CI4alkyl; hydroxy; hydroxy-CIalkyl; cyano; cyano-C1.6alkyl; or nitro, wherein the amino and hydroxyl moieties may optionally include a protecting group; R7 is: hydrogen; orCI1 4alkyl; R' is: hydrogen;C1. 4alkyl; halo-CI 4alkyl; halo; amino; amino-C1.4alkyl; hydroxy; hydroxy-C 6 alkyl; cyano; or cyano-C1.6alkyl, wherein the amino and hydroxyl moieties may optionally include a protecting group; Pg' is an optional amine protecting group; and Pg2 is an optional hydroxyl protecting group; the method comprising: reacting a phenyl boronate compound of formula m: 2 4 Pg 0 5
Rao' B7 6 ORa R OR HN H 2N O O
R8 m or a salt or solvate thereof, with a phenyl halide compound of formula e; OH R1 Y
R2 R3
N OH 1 Pg 0 e or a salt or solvate thereof, in the presence of chloro(crotyl)(tri-tert-butylphosphine)palladium(11), to form a compound of formula y;
FPg2 4 R
(R) N0 8 R1 O
R2 R3 R R7 NH 2
Pgi O
.0 or a salt or solvate thereof; and cyclizing compound v by forming an amide bond to make the compound o; or a salt or solvate thereof
3. The method of paragraph 1 or 2, further comprising reacting a compound of formula k 2 4 pg 05
7
R6 (R) OR NH O k pg$NH R8
or a salt or solvate thereof, with a boronating agent to form a compound of formula 1
P9'2 4 O 5
ORB R7 B OR R6 (R) OR NH O 0 pg1-NH Rg or a salt or solvate thereof; and removing the protecting group Pg from compound 1to form the compound of formula m; or a salt or solvate thereof.
4. The method of paragraph 3, further comprising: reacting a compound of formula h 4
HO R5 7 y '6-R
(R) OR H 2N O or a salt or solvate thereof, .0 with an amino acid of formula i
H OH Pg 1 N O Ra8 or a salt or solvate thereof, to form a compound of formula j 4
HO R5
y ~R 7
(R) OR H HN pg1-N O O 0 R8 or a salt or solvate thereof; and introducing a hydroxyl protecting group Pg 2 to compound j to form the compound of formula k; or a salt or solvate thereof.
5. The method of paragraph 4, further comprising: esterifying a compound of formula g
HO 5
R6 (R) OH H 2N O or a salt or solvate thereof, to form the compound of formula h; or a salt or solvate thereof.
6. The method of paragraph 5, further comprising: halogenating of a compound formula f 4
HO 5
7 ' 1 6 R (R) OH H 2N
or a salt or solvate thereof, .0 to form the compound of formula g; or a salt or solvate thereof.
7. The method of paragraph 1 or 2, further comprising: reducing a compound of formula d OH Ri Y
R2 R3
O to form the compound of formula e; or a salt or solvate thereof.
8. The method of paragraph 7, further comprising: reacting a compound of formula c OH Ri Y
3 R2 / R
PgIN OH H C or a salt or solvate thereof, with trioxane, to form the compound of formula d; or a salt or solvate thereof.
9. The method of paragraph 8, further comprising: halogenating a compound of formula a OH R1
R2 R3 OH H 2N O a or a salt or solvate thereof, to form a compound of formula b OH R1 y
R2 R3 OH H 2N .0 0 or a salt or solvate thereof; and introducing an amine protecting group to compound b to form the compound of formula j
or a salt or solvate thereof;
.5 10. The method of paragraph 1 or 2, further comprising: reacting the compound of formula o, or a salt or solvate thereof; with an alkylating reagent of formula p
R 9-X P or a salt or solvate thereof, to form a compound of formula q
4
Pg2
R2 R3 R6 (R) R HN
N (S) O O0
Pgi ORS 1
or a salt or solvate thereof; wherein; X is a leaving group; and
R' is: C1.4alkyl; halo-C1.4alky; hydroxyl-C1.4alkyl; amino-C1.4akyl, aminosulfonyl-C1.4alkyl; or Ci
4alkoxy-CI 4akyl, wherein the amino and hydroxyl moieties each may optionally include a protecting group.
11. The method of paragraph 10, further comprising: removing the amine protecting group Pgi, and optionally removing the hydroxyl protecting group Pg2 from the compound of formula q, or a salt or solvate thereof; to form a compound of formula r 4
R O HO 5
R2 R3 R6 (R) R HN
O OH R8 Pg1 0R or a salt or solvate thereof; .0 12. The method of paragraph 11, further comprising: reacting the compound of formula r, or a salt or solvate thereof;, with an amino acid reagent of formula s
HN -- r OH Rio
.5 or a salt or solvate thereof; to form a compound of formula t 4
R 9 HO 5R7
R2 R3 R6 (R) R O HN
Pg N O Rio O R8
or a salt or solvate thereof.
Claims (12)
1. A method of making an arylomycin ring of formula o:
4 5 O1Pg2 5 OH
R2 R3 R6 (R)l R HN
N 1a O O O Pg Ra
or a salt or solvate thereof, wherein: R is: hydrogen; or CI1 4alkyl; R, R2, R3, R4 , R', and R6 each independently is: hydrogen; CI1 4alkyl; halo-CI1 4alkyl; halo; amino; amino-C1.
4alkyl; hydroxy; hydroxy-CI 6alkyl; cyano; cyan-C1.6alkyl; or nitro, wherein the amino and hydroxyl moieties each may optionally include a protecting group; R7 is: hydrogen; or CI1 4 alkyl; R' is: hydrogen; CI 4 alkyl; halo-CI 4 alkyl; halo; amino; amino-C1.4alkyl; hydroxy; hydroxy-CI 6 alkyl; cyano; or cyano-C1.6alkyl, wherein the amino and hydroxyl moieties each may optionally include a protecting group; Pg' is an optional amine protecting group; and Pg 2 is an optional hydroxyl protecting group; the method comprising: cyclizing the compound of formula y:
Pg2 4 RO OH 0 R1 (R) 8
/ R3 R6 R7 NH2 R2
OH Y N (s) Pgi O
or a salt or solvate thereof, wherein: R, R1 , R2 , R 3, 4, R, R 6, R 7, R', Pg', and Pg 2 are as defined in the arylomycin ring of formula o; by forming an amide bond to make the arylomycin ring of formula o, or a salt or solvate thereof.
2. The method of claim 1, further comprising reacting a compound of formula k:
Pg 2 4 05 O 6
R6 (R) OR NH
pgi-NH O O R8 or a salt or solvate thereof, wherein : R, R4, R', R6, R, R', Pg', and Pg 2 are as defined in claim 1; and Y is halogen; with a boronating agent to form a compound of formula 1:
Pg 2 R 4 O R5
R0 Rao_'B 6 R7 Ra6 6 (R) OR H HN
pgi N 000 8
or a salt or solvate thereof, wherein: R, R4, R', R6, R, R', Pg', and Pg 2 are as defined in claim 1; and Ra is: hydrogen; or CI 4alkyl; and may be the same or different on each occurrence, or two Ra groups may form a C 2-6alkylene that, together with the atoms to which they are attached, may form a five- or six-membered ring; wherein the compound of formula 1, or a salt or solvate thereof, is used in making the compound of formula y, or a salt or solvate thereof.
3. The method of claim 2, further comprising: reacting a compound of formula h: 4
HO 5
7 Y '.
(R) OR H2 N O or a salt or solvate thereof, wherein: R, R4, R', R6, and R 7 are as defined in claim 1; and Y is as defined in claim 2; with an amino acid of formula i:
H OH Pg N O R8
or a salt or solvate thereof, wherein: R' and Pg' are as defined in claim 1; to form a compound of formula j: 4
HO 5 7
R6 (R) OR H NN HN Pg 1 - 0O R8 or a salt or solvate thereof, wherein: R, R4, R', R6, R, R', and Pg' are as defined in claim 1; and Y is as defined in claim 2; and introducing a hydroxyl protecting group Pg 2to the compound of formula ,or a salt or solvate thereof, to form the compound of formula k, or a salt or solvate thereof
4. The method of claim 3, further comprising: esterifying a compound of formula g: 4
HO 5 7
6 R (R) OH H2 N 0 or a salt or solvate thereof, wherein: R , R6, and R7 are as defined in claim 1; and
Y is as defined in claim 2; to form the compound of formula h, or a salt or solvate thereof.
5. The method of claim 4, further comprising: halogenating a compound of formula f: 4
HO 5 7
R6 (R) OH H 2N
or a salt or solvate thereof, wherein: 4, R5, R6, and R7 are as defined in claim 1; to form the compound of formula g, or a salt or solvate thereof.
6. The method of claim 1, further comprising: reducing a compound of formula d: OH R1 Y
R2 R3
Pg ' N O o0,
or a salt or solvate thereof, wherein: R', R2, R3, and Pg' are as defined in claim 1; and Y is halogen; to form the compound of formula e: OH R1 Y
R2 R3 OH N 1 Pg 0 e or a salt or solvate thereof; wherein: R, R2, R3, and Pg' are as defined in claim 1; and Y is as defined in the compound of formula d; wherein the compound of formula e, or a salt or solvate thereof, is used in making the compound of formula y, or a salt or solvate thereof.
7. The method of claim 6, further comprising: reacting a compound of formula c: OH Ri Y
R2 / R3 Pgi,'NOH H 0 C
or a salt or solvate thereof, wherein: R', R2, R, and Pg' are as defined in claim 1; and Y is as defined in claim 6; with trioxane to form the compound of formula d, or a salt or solvate thereof
8. The method of claim 7, further comprising: halogenating a compound of formula a: OH R1
R2 R3 OH H2 N O a, or a salt or solvate thereof, wherein: R', R2, and R3 are as defined in claim 1; to form a compound of formula b: OH R1 y
R2' R3 OH H2 N b
or a salt or solvate thereof, wherein: R', R2, and R 3 are as defined in claim 1; and Y is as defined in claim 6; and introducing an amine protecting group to the compound of formula b, or a salt or solvate thereof, to form the compound of formula c, or a salt or solvate thereof.
9. The method of claim 1, further comprising: reacting the arylomycin ring of formula o, or a salt or solvate thereof, with an alkylating reagent of formula P:
R 9-X P,
or a salt or solvate thereof, wherein: R9 is: CI1 4 alkyl; halo-C 4 alkyl; hydroxyl-CI1 4 akyl; amino-C 4 alkyl, aminosulfonyl-CI1 4akyl; or C1 4 alkoxy-C1
. 4alkyl, wherein the amino and hydroxyl moieties each may optionally include a protecting group; and X is a leaving group; to form a compound of formula q:
4
R R Pg2 R1 R7 5 R2 R3 R6 (R) R HN (s) O O g
Pg1 0 R8
or a salt or solvate thereof; wherein; R, R1 , R2 , R 3, 4, R, R 6, R 7, R', Pg', and Pg 2 are as defined in claim 1; and R9 is as defined in the compound of formula p.
10. The method of claim 9, further comprising: removing the amine protecting group Pg', and optionally removing the hydroxyl protecting group Pg 2 from the compound of formula q, or a salt or solvate thereof, to form a compound of formula r: 4
R 9 HO 5 R7
o R R2 R3 R6 (R) R HN
N O O H 0 R8
or a salt or solvate thereof, wherein: R, R 1, R2 , R 3, 4, R, R 6, R 7, R', and R 9 are as defined in claim 1 or 9.
11. The method of claim 10, further comprising: reacting the compound of formula r, or a salt or solvate thereof, with an amino acid of formula s: Pg O
HN -- OH Ro0s
or a salt or solvate thereof; wherein: Pg' is as defined in claim 1; and R" is: hydroxyl-C1. 4 alkyl; amino-C1. 4alkyl; aminosulfonyl-C1. 4alkyl; or C1. 4 alkoxy-C1. 4alkyl, wherein the amino and hydroxyl moieties each may optionally include a protecting group; to form a compound of formula t: 4
RL 9 HO 1 5R7
R2 R3 R6(R) R O HN
Pg N ( O O Rio 0 R8
or a salt or solvate thereof, wherein: R, RR 2, R 3, R, R, R6, R 7, R, R, ,and Pg' are as defined in claim 1 or 9; and R 1 0is as defined in the compound of formula s.
12. An arylomycin ring of formula o:
0 5 OH R9 R7
R2 R3 R6 (R) R HN (S) "T O O and~gareadefindincaim1 Pg1 O R8
or a salt or solvate thereof, prepared by the method of any one of claims 1 to 8, wherein R1, R, R , R , R R, R8, Pg' and Pg2 are as defined in claim 1.
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KR102589474B1 (en) | 2023-10-16 |
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HRP20211495T1 (en) | 2021-12-24 |
BR112019020112A2 (en) | 2020-05-05 |
SG11201908932SA (en) | 2019-10-30 |
KR20190133033A (en) | 2019-11-29 |
CN117777229A (en) | 2024-03-29 |
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